bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Enhanced autophagic-lysosomal activity and increased BAG3-

mediated selective macroautophagy as adaptive response of neuronal

cells to chronic oxidative stress

Debapriya Chakraborty1, Vanessa Felzen1, Christof Hiebel1, Elisabeth Stürner1, Natarajan

Perumal2, Caroline Manicam2, Elisabeth Sehn3, Franz Grus2, Uwe Wolfrum3, Christian Behl1*

1Institute of Pathobiochemistry, University Medical Center Mainz of the Johannes Gutenberg

University, 55099 Mainz, Germany

2Experimental and Translational Ophthalmology, University Medical Center Mainz, 55131 Mainz,

Germany

3 Institute for Molecular Physiology, Johannes Gutenberg University, 55128 Mainz, Germany

E-mail addresses of authors:

D. Chakraborty: [email protected]; V. Felzen: [email protected]; C. Hiebel:

[email protected]; E. Stürner: [email protected]; N. Perumal: nperumal@eye-

research.org; C. Manicam: [email protected]; E. Sehn: sehn@uni-

mainz.de; F. Grus: [email protected]; U. Wolfrum: [email protected];

*Correspondence to

Christian Behl, PhD

Institute of Pathobiochemistry

University Medical Center of the Johannes Gutenberg University

Duesbergweg 6, D-55099 Mainz

[email protected]

Tel.: +49-6131-39-25890; Fax: +49-6131-39-25792

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Abstract

Oxidative stress and a disturbed cellular protein homeostasis (proteostasis) belong to the

most important hallmarks of aging and of neurodegenerative disorders. The proteasomal and

autophagic-lysosomal degradation pathways are key measures to maintain proteostasis. Here,

we report that hippocampal cells selected for full adaptation and resistance to oxidative stress

induced by hydrogen peroxide (oxidative stress-resistant cells, OxSR cells) showed a massive

increase in the expression of components of the cellular autophagic-lysosomal network and a

significantly higher overall autophagic activity. A comparative expression analysis revealed that

distinct key regulators of autophagy are upregulated in OxSR cells. The observed adaptive

autophagic response was found to be independent of the upstream autophagy regulator mTOR

but is accompanied by a significant upregulation of further downstream components of the

canonical autophagy network such as Beclin1, WIPI1 and the transmembrane ATG9 proteins.

Interestingly, the expression of the HSP70 co-chaperone BAG3, mediator of BAG3-mediated

selective macroautophagy and highly relevant for the clearance of aggregated proteins in cells

was found to be increased in OxSR cells that were consequently able to effectively overcome

proteotoxic stress. Overexpression of BAG3 in oxidative stress-sensitive HT22 wildtype cells

partly established the vesicular phenotype and the enhanced autophagic flux seen in OxSR cells

suggesting that BAG3 takes over a key part in the adaptation process. A full proteome analysis

demonstrated additional changes in the expression of mitochondrial proteins, metabolic enzymes

and different pathway regulators in OxSR cells as consequence of the adaptation to oxidative

stress in addition to autophagy-related proteins. Taken together, this analysis revealed a wide

variety of pathways and players that act as adaptive response to chronic redox stress in neuronal

cells.

Key words

Autophagy, Protein homeostasis, Adaptation, Oxidative stress, BAG3

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Abbreviations ATG, Autophagy related; BAG1, BCL2 Associated Athanogene 1; BAG3, BCL2 Associated

Athanogene 3; BECN1, Beclin1; BNIP3, BCL2 interacting protein 3; BafA1, Bafilomycin A1;

CTSD, Cathepsin D; CV, Canavanine; DLP1, Dynamin-like protein 1; Hsp70, Heat shock protein

70; LAMP1, Lysosomal‐associated membrane protein 1; LAMP2, Lysosomal‐associated

membrane protein 2; LC3, Light chain 3 protein; LETM, Leucine zipper and EF-hand containing

transmembrane protein; LFQ, Label-free quantification; mTOR, Mammalian target of rapamycin;

MTT, (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide); NS, Nonsense; PIK3C3,

Class III PI3‐kinase; PolyUB, Polyubiquitin; RAB18, Member RAS oncogene; Rapa, Rapamycin;

siRNA, Small interfering RNA; TUB, Tubulin; TFEB, Transcription factor EB; TEM, Transmission

electron microscopy; WIPI1, WD repeat domain phosphoinositide-interacting protein 1

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1. Introduction Oxidative stress, the accumulation of reactive oxygen species which chemically modify

and damage proteins, lipids and DNA disturbs cellular homeostasis and has been linked to aging

and the pathogenesis of diseases such as cancer and neurodegeneration [1]. Neuronal disorders

like Alzheimer’s Disease (AD), Parkinson’s Disease and Amyotrophic Lateral Sclerosis (ALS)

show increased levels of oxidation end products in affected brain regions [2], [3]. Strikingly, in AD

nerve cell death is not equally distributed throughout the brain but it is rather occurring in the

pyramidal neurons of the entorhinal and the inferior temporal cortex, the hippocampus and the

amygdala while other brain regions such as the cerebellum show resistance [2], [4], [5]. Some

aspects characterizing the basis for this selective vulnerability of neurons in distinct brain regions

were addressed before and pinned down to the ability to actually resist oxidative stress [6]. Also,

in other neurodegeneration pathologies selective vulnerability (and resistance) is observed [7]. A

highly upregulated antioxidant defense is also linked to the progression of certain tumor types [8],

[9]. Though oxidative stress resistance appears to be disadvantageous in the context of tumor

therapy, it could be beneficial in the attempt to support long-term survival of cells that are

particularly sensitive to oxidative stress, such as post-mitotic neuronal cells. Therefore, it would

be a huge step forward to uncover the molecular basis of an adaptation to oxidative stress and

redox stress-associated pathological mechanisms.

To overcome challenges of the cellular homeostasis network during elevated cellular

stress, autophagy plays a crucial role. In this process, double-membraned vesicles, called

autophagosomes, are formed which sequester large protein complexes and organelles and finally

deliver them to lysosomes for degradation [10]. Functionally, autophagy is an intracellular

recycling process that guarantees energy supply by generating amino acid building blocks during

low nutritional condition [11]. Additionally, autophagy works as an essential stress-adaptive

response and rescue mechanism by selective degradation of damaged organelles, protein

aggregates and intracellular pathogens [12], [13]. Recently, autophagy was found to be a survival

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response against oxidative stress in bone marrow–derived mesenchymal stromal cells [14] and,

moreover, the activation of autophagy can protect against oxidative stress-induced neuronal

damage in adult rats [15].

In the context of autophagy and oxidative stress, previously it has been shown that the

HSP70 co-chaperone Bcl2-associated athanogene 3 (BAG3) is highly upregulated in many

aggressive tumor types and a link between oxidative stress, enhanced autophagy and BAG3

expression is described for several tumor cells [16] [17], [18], [19]. BAG3 was identified as a key

player in the BAG3-mediated selective macroautophagy [20] and established as an important

partner of the cellular proteostasis network under oxidative and proteotoxic stress as well as in

aging conditions [21], [22], [23], [24].

The concept of oxidative stress adaptation has been successfully applied by different

groups employing clonal neuronal cells lines, such as rat pheochromocytoma PC12 and mouse

clonal hippocampal HT22 cells [25], [26], [27], [28], [29]. Previous studies mainly focusing on the

redox stress-resistance phenotype and its reversal in PC12 and HT22 cells revealed key roles for

the transcription factor NF-B, sphingolipids and increased levels of antioxidant enzymes to

provide the oxidative stress resistance phenotype [26], [27], [28]. In our current study we now

systematically analyzed molecular and functional changes in HT22 cells stably adapted to redox

stress as induced by hydrogen peroxide (here called OxSR cells) with a particular focus on the

autophagy network. We observed an increased autophagic-lysosomal and a decreased

proteasomal activity in OxSR cells and analyzed in detail the expression patterns of key

autophagy regulators. We identified that the expression of BAG3 and BAG3-mediated selective

macroautophagy is upregulated suggesting BAG3 thus may play a particular role in oxidative

stress adapted-cells. Finally, a whole proteome comparison between wild type and OxSR cells

revealed a wide range of alterations of key proteins involved in different cellular pathways in

addition to the autophagy regulators demonstrating the massive impact of chronic redox stress

on the protein expression pattern during oxidative stress adaptation.

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2. Material & methods

2.1 Cell culture

Wild type HT22 cell line (HT22-WT), a cloned mouse hippocampal neuronal cell line which is

very susceptible to oxidative stress [28], [30] was used as control cell line. HT22 cells resistant to

hydrogen peroxide induced oxidative stress, here called OxSR cells, were established by clonal

selection. The details of the selection procedure have been described elsewhere [31]. Both cell

lines were cultured in Dulbecco’s modified Eagle’s medium containing 10 % fetal calf serum

(FCS), 1 mM sodium pyruvate and 1x penicillin/streptomycin (Invitrogen, Karlsruhe, Germany).

To maintain the resistant phenotype, 450 µM of H2O2 f.c. (Sigma, Deisenhofen, Germany) was

added twice a week to the OxSR cells. Prior to performing experiments, OxSR cells were cultured

for three days without H2O2 and medium was exchanged daily to remove residual toxins. Although

oxidative stress-resistant mouse hippocampal HT22 cells have been employed before, for the

present study we initially reconfirmed the previously observed characteristics of the cell clones

used here. So, the cell proliferation rates of the different cell clones were estimated by MTT assay.

Consistent with previous findings [31] the growth rate of the OxSR cells was found to be lower

than that of the HT22-WT cells (supplementary figure S1A) confirming that increased vitality and

oxidative stress resistance of the selected clones was not simply based on a higher proliferation

rate.

2.2 Pharmacological agents and antibodies

Stock solutions of Bafilomycin A1 (LC Laboratories, B-1080), MG132 (Calbiochem, 474790)

and Rapamycin (Enzo, BML-A275-0025) were prepared in DMSO (Roth, A994.2). Stock solution

of Canavanine (Santa Cruz Biotech, sc-202983A) was prepared in distilled H2O.

Antibody sources were as follows: for BAG1 (Abcam, ab7976), BAG3 (Proteintech Group,

10599-1-AP), BECN1 (Cellsignaling, 3495), CTSD (Abcam, ab75852), DLP1 (BD Transduction

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Laboratories,611113), LAMP2 (DSHB Biology, ABL-93), LC3B (Nanotools, 0260-100), LC3B

(Sigma, L7543), Phospho mTOR (Abcam, ab109268), mTOR (Calbiochem, OP97), p62 (Progen,

GP62-C), PIK3C3 (Cellsignaling, 4263), Poly-Ubiquitin (Dako, Z0458), RAB18 (Sigma,

SAB4200173), Tubulin (Millipore, MAB1637), Tubulin (Sigma, T9026), TFEB (Proteintech Group,

13372-1-AP), Vimentin (SCBT, sc-373717), WIPI1 (Sigma, HPA007493).

2.3 Plasmids, siRNAs and transfection method

Expression plasmid for mouse FLAG tagged BAG3 (pFLAG-BAG3) was constructed by

cloning partial mouse BAG3 cDNA containing the whole CDS into pEGFP‐N1 (Clontech). Forward

primer sequence used to clone BAG3 plasmid is 5'-AAAGGATCCAGCGCCGCCACCC-3' and the

reverse primer sequence is 5'-GACTCTAGATCACTAGGGAGCCACCAGGTTGC-3'. After vector

linearization with BamHI and XbaI, PCR products were inserted using the In‐Fusion reaction

according to manufacturer's protocol (Clontech).

Two independent sets of siRNA against BAG3 were purchased from Eurofins MWG

Operon with 3′‐dTdT overhangs. Sequence of used siRNA1 is 5'-AAUACCUGAUGAUCG AAGA-

3' and siRNA2 is 5'-AUACCUGAUGAUCGAAGAG-3'. Generally, cells were transfected by mixing

20 µg of each of the siRNA as duplex. In all knockdown experiments, same amounts of siRNA

targeting a nonsense sequence (5'-AUUCUCCGAACGUGUCACG-3') were transfected as

control.

Cells were transfected by electroporation using the Amaxa Nucleofector I (program U‐24)

and standard electroporation cuvettes (Sigma). Electroporation buffer details are mentioned

elsewhere [21].

2.4 Immunoblotting and immunocytochemistry

Western blot analysis and inmmunocytochemistry were carried out as previously

described [21]. Blots were developed with the Fusion-SL 3500 WL system (Peqlab, Erlangen,

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Germany) and densitometry analysis was performed using Aida Image Analyzer v.4.26 software

(Raytest, Straubenhardt, Germany). For the labelling of the lysosomes and acidic vacuoles, the

fluorescent dye LysoTracker was used. Cells (cultured on 24-well plates with coverslips) were

incubated with 100 nM LysoTracker Red DND-99 (Thermo scientific, L7528) in culture medium

for 1 h under incubator conditions and then fixed with 4 % PFA. Cells for immunocytochemistry

were analyzed using a confocal laser-scanning microscope (LSM710, Zeiss) and images were

processed with Adobe Photoshop CS5 (San Jose, CA, USA).

2.5 Transmission electron microscopy

Sample preparation and transmission electron microscopy (TEM) analysis were carried

out as previously described [21] and images were processed with Adobe Photoshop CS5.

2.6 Proteomic analysis

Proteomic analysis was executed in different distinct steps such as protein extraction,

sample preparation, 1-dimensional gel electrophoresis (1DE), mass spectrometry (MS) based

discovery proteomics analysis, bioinformatics and functional annotation and pathways analyses.

General approaches used for the analysis were adapted from previously published papers [32],

[33], [34], [35], [36], [37], [38], [39]. Details of the individual techniques employed for this paper

are described in supplementary file S3 “proteomics methods”.

2.7 Quantitative real time PCR array

RNA extraction, cDNA synthesis and Quantitative real‐time PCR (qPCR) for HT22-WT

and OxSR cells were performed by the protocol previously described [40]. A commercial ready to

use primer mix in 96 well format (Biomol, MATPL-1) containing total 88 different genes involved

in autophagy were used for qPCR array. PCR cycles were set according to the manufacturer’s

protocol. CT values obtained from Quantitative Real‐Time PCR data were applied to REST

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software for calculating the relative fold change in expression of each gene [41]. Actin was used

as a reference gene. A fold change of +1.5 or -0.6 is considered as regulated gene.

2.8 Measurement of proteasome activity

This procedure is adapted from previous publication [42]. Briefly, cells were washed with

ice cold PBS and lysed in lysis buffer (50 mM HEPES, pH 7.8, 10 mM NaCl, 1.5 mM MgCl2, 1

mM EDTA, 1 mM EGTA, 250 mM sucrose, and 5 mM DTT) at 4°C. The homogenates were

centrifuged at 10 000 g for 15 min at 4°C. Supernatants were collected and normalized to protein

content. Enzymatic reaction was started by mixing active cell extracts (containing 15 μg protein

determined by BCA) with 100 μl of assay buffer. Assay buffer composition is same as lysis buffer

only supplemented with ATP (2 mM) and proteasome substrate (100 μM, Suc‐LLVY‐AMC,

Sigma). AMC fluorescence released by cleavage of substrate by proteolytic activity was recorded

in a black 96‐well plate after 60 min incubation at 37°C using the Victor 3V Multilabel counter

(Perkin Elmer). Specific proteasomal activity was determined by subtracting unspecific AMC

fluorescence obtained in the presence of proteasome inhibitor MG132 (20 μM). Results are

expressed as % AMC release.

2.9 Cell proliferation assay

The growth rate of HT22-WT and OxSR cells were determined by the analysis of cellular

metabolic activity. The ability of cells to reduce yellow coloured water soluble MTT to a blue violet

coloured water insoluble formazan crystals were measured colorimetrically over nine alternate

days. The detailed procedure is described elsewhere [31].

2.10 Statistical analysis

Statistical significance of all quantified Western blots, lysotracker staining and qPCR data

was determined by unpaired t‐test using GraphPad Prism 7 (GraphPad Inc., San Diego, USA).

Growth curve for cell proliferation assay was analyzed by two-way ANOVA with the same

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software. Statistical significance was accepted at a level of p<0.05. The results are expressed as

mean ± S.E.M. The proteomics data were statistically analyzed with Perseus software (version

1.6.1.0). The degree of variances between the biological replicates and groups were assessed

by Pearson's correlation analysis and Student’s two-sided t-test was used for the groups’

comparison to identify the significantly differentially abundant proteins. Details are maintained in

supplementary file S3 “proteomics methods”.

3. Results

3.1 Autophagosomes, autophagic flux and lysosomal activity are increased in OxSR cells

Based on previous findings that HT22 cells resistant to H2O2 (OxSR) show an

upregulation of the lysosomal marker LAMP1 compared to oxidative stress-sensitive HT22

wildtype cells (HT22-WT) [28], we analyzed the cellular vesicular ultrastructure in detail. TEM

revealed the presence of an intensive vesicular network in OxSR cells and a higher number and

size of double-membrane autophagosomes as well as lysosomes in OxSR cells, suggesting an

enhanced autophagic-lysosomal activity (Figure 1A). Therefore, we next investigated the baseline

autophagic flux in OxSR cells in presence of BafA1 which inhibits fusion of autophagosomes and

lysosomes. We observed a significantly elevated autophagic flux, the enhanced accumulation of

LC3B-II as well as p62 upon BafA1 treatment in OxSR cells compared to HT22-WT cells (Figure

1B-D). Consistently, immunostainings showed a generally upregulated lysosomal activity in OxSR

cells indicated by the lysosomal enzyme marker cathepsin D (Figure 1E). Nuclear translocation

of TFEB is known to have a pivotal role in upregulation of autophagy and lysosomal biogenesis

[43]. TFEB was found to be localized mainly in the cytoplasm of HT22-WT cells and almost

exclusively translocated to the nucleus in OxSR cells as shown by immunocytochemistry

(Supplementary Figure S1B) pointing towards an ongoing transcription of TFEB target genes in

OxSR cells supporting the continuous autophagic activity.

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3.2 OxSR cells show enhanced expression of several key autophagy regulators but mTOR

expression and phosphorylation status is unchanged

Next, we focused on the expression of certain key regulators of canonical autophagy in OxSR

cells (as indicated in the schematic diagram in Figure 2A). Employing Western blotting no

changes in the phosphorylation status of the main regulator of canonical autophagy mTOR (ratio

of p-mTOR to mTOR as measure of mTOR-dependent autophagy induction) was detectable in

the OxSR cells (Figure 2B and C). To check the responsiveness of the mTOR-regulated

autophagy pathway in OxSR cells, we treated the cells with rapamycin and monitored autophagic

flux after co-treatment with BafA1. We found that rapamycin significantly increases autophagic

flux in OxSR cells indicating that the mTOR-mediated autophagic pathway is still principally

inducible in this cell line (Figure 2H and I) but obviously is not activated under basal conditions in

OxSR cells adapted to redox stress.

Another upstream regulator of autophagy is the PI3KC3/BECN1 complex required for the

recruitment of PI(3)P during autophagosome generation. Interestingly, we found an almost 2.5-

fold higher BECN1 protein level in OxSR cells indicating that the BECN1 complex is highly active

in oxidative stress-adapted cells (Figure 2B and D). WIPI1 acts downstream as PI(3)P

effectors for proper membrane rearrangement [44], [45] and consistent with the observed

increased protein level of BECN1, Western blot analysis indeed revealed also upregulated levels

of both PI3KC3 and WIPI-1 in OxSR cells (Figure 2B, E and F). Moreover, RAB18 was found to

be upregulated in its expression approximately 1.6-fold in OxSR cells (Figure 2B and G). The

small Rab GTPase RAB18 is a known key regulator of ER-Golgi membrane trafficking, involved

in cellular lipid metabolism and as recently shown also shown a positive modulator of autophagy

[46], [47], [48]. Taken together, in OxSR cells we found a significant upregulation of the expression

of distinct key proteins of canonical autophagy regulation comprising BECN1, WIPI1 and PI3KC3

as well as the positive autophagy regulator RAB18.

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3.3 Autophagy qPCR array reveals a high upregulation of ATG9 mRNA in OxSR cells

Employing a qPCR array representing a wide range of genes involved in the direct

regulation of various stages of the autophagic process itself as well as candidates that are not

part of the core canonical autophagy machinery, we found a highly differential mRNA expression

pattern comparing OxSR and WT cells. OxSR cells showed significantly higher mRNA expression

of certain ATG proteins, including ATG10, ATG12, ATG5, as well as GABRAPL2 and AKT1S

(Table 1). Moreover, consistently with our Western blot findings (see Figure 2), the qPCR also

showed an elevated level of BECN1 and WIPI1 mRNA in OxSR cells (Table 1). Further, the

expression of the lysosomal marker LAMP1 mRNA was upregulated in OxSR cells, confirming

earlier observation in H2O2-resistant HT22 cells (Table 1) [28].

Most significantly, we also found an over 30-fold upregulation of the mRNA expression

of ATG9B in OxSR cells (Table 1). ATG9 proteins are essential for phagophore maturation

(meaning early steps in autophagosome generation) and vesicle elongation and also

determines the size of autophagosomes by acting as a lipid carrier delivering lipids to the

growing phagophore [49], [50], [51], [52]. In addition, also a higher expression of the SEC23a

and SEC23b mRNA was observed in OxSR cells (Table 1). SEC protein family members are

important for the formation of specialized transport vesicles from ER to autophagosome

biogenesis and selection of specific cargo molecules [53], [54].

The PCR mRNA array further revealed a significant increase in the mRNA expression of

BNIP3 (6-fold) and BNIP3 is known to regulate mitophagy, the autophagic clearance process of

damaged mitochondria (Table 1) [55]. LETM1 and 2, which are not directly related to autophagy

but required to maintain mitochondrial ion homeostasis and morphology [56], [57] were also

found to be highly upregulated in OxSR cells in their expression (Table 1) linking oxidative

stress adaptation also to altered mitochondrial function; this link is further confirmed by full

proteome analysis (see 3.7 below). Consistent with these data, the observed alteration of overall

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mitochondrial morphology in OxSR cells is also supported by highly elevated levels of DLP1,

which is responsible for mitochondrial fission, as detected by Western blot analysis

(Supplementary Figure S1C and D).

3.4 OxSR cells can handle more effectively proteotoxicity

Next, we investigated how effectively OxSR cells can handle disturbances of the proteostasis

network. To reproducibly induce protein stress, we employed the compound canavanine (CV), an

arginine analogue which disturbs protein homeostasis by interfering with protein translation.

Western blot analysis revealed an increased accumulation of polyubiquitinated degradation-prone

proteins in HT22-WT but not in OxSR cells after 12 h treatment of the cells with CV (Figure 3A

and B). Since the proteasomal activity in OxSR cells was lower compared to HT22 WT cells (see

below and Supplementary Figure S1E) the increased ability of the OxSR cells to cope with

proteotoxic stress as indicated by the accumulation of polyubiquitinated proteins could be a direct

result of an increased autophagic clearance activity.

3.5 BAG1/BAG3 expression switch in OxSR cells

In OxSR cells chronically adapted to oxidative stress we observed a switch from BAG1 to

BAG3 expression as previously already seen in human primary fibroblasts and neurons under

acute redox stress and during aging [21], [58]. BAG3 expression is increased in OxSR cells

compared to HT22-WT cells, while the expression of BAG1L in OxSR cells was decreased as

detected by Western blotting (Figure 3C-E); BAG1L is the same isoform of BAG1 which was

detected to be decreased in aged cells or cells after acute oxidative stress treatment [21]. Taken

together, BAG3 and BAG1 (isoform BAG1L) expression are reciprocally regulated in OxSR cells.

Next, the proteasomal chymotrypsin‐like activity in OxSR and HT22-WT cells was analyzed and

found to be decreased in OxSR cells (Supplementary Figure S1E). These results suggest that

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OxSR cells depend more on the autophagic system (driven by BAG3 [21]) rather than on the

proteasomal system (driven by BAG1) for protein degradation. To further confirm the recruitment

of BAG3 into the proteostasis network of OxSR cells proteasomal activit was inhibited by MG132,

an efficient stimulus of protein aggresome formation [21]. The observed colocalization of BAG3

with vimentin-positive perinuclear aggresomes after pharmacological proteasome inhibition in the

OxSR cells (Figure 3F) suggests an enhanced activity of BAG3-mediated aggresome targeting

and autophagy.

3.6 BAG3 overexpression in HT22-WT cells leads to increased autophagic flux and

lysosomal rearrangement, BAG3 depletion in OxSR cells results in reduced autophagic

flux

To clarify a direct participation of BAG3-mediated selective macroautophagy in the enhanced

overall autophagic activity and the lysosomal phenotype of OxSR cells, we overexpressed BAG3

in HT22-WT cells. HT22-WT cells following transfection with a BAG3 expression construct

showed a significantly increased autophagic flux (Figure 4A, B and D). Intriguingly, along with

overexpression of BAG3 also the protein levels of the lysosomal membrane protein LAMP2 were

found to be strongly enhanced (Figure 4A and 4C). This suggests that BAG3 expression can have

a direct effect on lysosomes. Finally, lysosomal compartments were analyzed by LysoTracker

staining in HT22-WT (as controls), HT22-WT cells transfected with empty vector (HT22-WTev),

HT22-WT cells overexpressing BAG3 (HT22-WTBAG3) and OxSR cells. Perinuclear lysosomes

were found in HT22-WT and HT22-WTeV cells (controls), however, BAG3-overexpressing HT22-

WTBAG3 cells showed an elevated number of lysosomes with cellular distribution comparable to

that in OxSR cells (Figure 4I). Quantification showed that also the total number of cells showing

distinguishable acidic vacuolar structure is significantly elevated in HT22-WTBAG3 compared to

HT22-WT and HT22-WTeV and is comparable to OxSR cells (Figure 4H and I).

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In addition, after knockdown of BAG3 in OxSR cells, autophagic flux was analyzed by

determining the accumulation of LC3B-II after treatment with BafA1 by Western blot. Upon

knockdown of BAG3 via siRNA a significant reduction of the autophagic flux was found in OxSR

cells (Figure 4E-G), whereas the downregulation of BAG3 by siRNA showed no change in

autophagic flux of HT22-WT cells (data not shown). Taken together these results strongly support

the role of BAG3 and BAG3-mediated selective macroautophagy in the adaptation of OxSR cells

to chronic redox stress.

3.7 Total proteome analysis underlines differential expression of proteins involved in

autophagy, mitochondrial function and metabolism

Finally, to analyze changes in the global proteome in OxSR cells (as compared to HT22-WT)

we performed a bottom-up mass spectrometry-based discovery proteomics analysis. Label-free

quantification (LFQ) analysis of the triplicates of both cell lines employing a false discovery rate

(FDR) of 1% identified a total of 1121 proteins (the complete dataset is included in Supplementary

file S4A “Proteomics data”). Subsequently, we identified the proteins that exhibited significant

variations between OxSR and HT22-WT cells. For this, the experimental reproducibility of the

LFQ between the replicates was examined employing Pearson's correlation coefficients, which

demonstrated excellent biological reproducibility with an average R value of 0.97 ± 0.01 and R of

0.93 ± 0.01 between the two cell lines. Data is represented in the scatter plots of the intensity

distribution in one replicate relative to another (Supplementary file S4B “Proteomics data”).

Among the identified proteins, 176 were differentially expressed, with 87 up-regulated and 89

down-regulated proteins (Supplementary file S4C “Proteomics data”). Further clustering of these

differentially expressed proteins depicts the distinct patterns of the proteome presented as a heat

map with unsupervised hierarchical clustering (Figure 5A). Closer examination of these protein

clusters revealed significant changes in several cellular functions (Figure 5B and Supplementary

15 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

file S4D “Proteomics data”). Endoplasmic reticulum stress response, fatty acid metabolism,

synthesis of reactive oxygen species, glycolysis, mitochondrial disorder, oxidative stress,

autophagic cell death, neuronal cell death, autophagy and cell survival of neurons represent the

top ten most significant functional changes implicated in OxSR cells in comparison to the oxidative

stress-sensitive HT22-WT cells.

Finally, in an effort to further explore protein-protein interaction pathways (PPIs) of the proteins

identified to be differentially expressed, functional pathway enrichment was determined

employing the Ingenuity Pathway Analysis (v01-04, IPA; Ingenuity QIAGEN Redwood City, CA)

tool. Consistently, a large majority of these proteins were found to be actively involved in the

process of autophagy (14 proteins) but also linked to mitochondrial function and disorders (16

proteins) and oxidative stress/redox signaling (7 proteins) (Supplementary Figure S2 and the

complete list to be found in Supplementary file S4E “Proteomics data”).

4. Discussion

A disturbed protein homeostasis, proteotoxic and oxidative stress are hallmarks of

neurodegeneration and aging [59], [60], [61]. Autophagy is described as a physiological process

involved in antioxidant defense [62] and autophagy deficiency clearly results in neuronal loss and

neurodegeneration in mice [63]. On the other hand, induction of autophagy is shown to alleviate

oxidative stress in myocardial ischemia/reperfusion Injury [64].

The adaptation to oxidative stress is a highly relevant process and some adaptive

pathways focusing on antioxidant defense systems and mitochondrial and metabolic adaptations

have been described to be constantly activated in neuronal cells resistant to oxidative stress as

well as in AD tissue [26], [29], [6]. Moreover, oxidative stress resistance has been linked to failure

of anticancer therapy and here a particular role of upregulated autophagy and BAG3 has been

proposed in various tumor types [16], [65], [66], [67].

16 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Based on the knowledge that dysregulated autophagy is actively involved in

neurodegeneration [68], [69] combined with previous findings on mouse hippocampal HT22 cells

fully adapted to high concentrations of H2O2 (OxSR cells) [28], we describe here in detail the

molecular changes associated with redox stress adaptation in neuronal cells. To do so, we

engaged different expression and functional studies including morphological parameters obtained

by TEM, investigation of autophagic flux and global proteome analysis using mass spectrometry.

We found a significantly increased autophagic activity in the cells adapted to chronic

oxidative stress (OxSR cells) (Figure 1) and on the other hand a reduced proteasomal function

(Supplementary Figure S1E) suggesting that autophagy may serve as the preferred protein

degradation pathway during oxidative stress challenge. We identified several key proteins

involved in autophagy regulation that showed a significantly altered expression. ROS production

i.e. oxidative stress is known to inhibit mTORC1 [64], [70], the major regulatory complex for

autophagy induction. Interestingly, in OxSR cells the increase in autophagy under chronic

oxidative stress is not mediated via mTOR inhibition, whereas the classical BECN1/PI3K3C3

complex obviously is involved and highly upregulated in their expression in OxSR cells (Figure

2). Moreover, RAB18 expression is enhanced in OxSR cells (Figure 2). This finding is consistent

with the recent description of RAB18 being a positive autophagy regulator [48] and a role of

RAB18 in lipid metabolism, which enables enhanced lipid recruitment for autophagosome

formation [71].

In qPCR analysis we observed a massively increased expression of ATG9B in OxSR cells

(Table 1). ATG9 is an essential ATG family protein required for phagophore formation and exists

in two homologues referred to as ATG9A and ATG9B. Trafficking of ATG9 from the Golgi

apparatus to the site of autophagosome formation following autophagy induction (for instance by

starvation) is reported to be dependent on PI3KC3 activity and negatively affected by PI3KC3

inhibition [72]. Therefore, it could be argued that upregulated ATG9B may work in concert with

PI3KC3 in OxSR to promote autophagy. Leow et al. recently suggested that also sublethal acute

17 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

oxidative stress can specifically induce ATG9B expression [73]. Furthermore, it is reported that

ATG9 not only just acts as an autophagic membrane protein, but also upregulates autophagy

induction via the JNK pathway by interacting with tumor necrosis factor receptor-associated factor

2 (dTRAF2) under oxidative stress condition [74]. In fact, ATG9 could be a key factor for the

observed significantly enhanced autophagy activity in OxSR cells, since it can ensure the

supply with membrane fragments early in autophagosome formation [75].

During cellular stress, the HSP70 chaperone system is a key player to maintain protein

homeostasis together with its co-chaperones BAG1 (for proteosomal degradation) and BAG3 (for

autophagic degradation). OxSR cells demonstrate an upregulated BAG3 accompanied with

downregulated BAG1L expression (“BAG1/BAG3-switch”) (Figure 3) and cope with a disturbed

proteostasis induced by canavanine more effectively. Also BAG3-positive aggresomes are found

upon proteasomal inhibition as previously observed (Figure 3) [23]. Most interestingly, the

overexpression of BAG3 causes a lysosomal rearrangement in HT22-WT cells that closely

resembles the distribution (and numbers) of lysosomes seen in OxSR cells (Figure 4). The

observed rearrangement of the lysosomal compartment by BAG3 may then have also functional

consequences on the autophagic flux since LC3B-II flux was increased in HT22-WT cells following

overexpression of BAG3 (Figure 4). Our results are consistent with recent observations that the

lysosomal biogenesis is increased under sub-lethal acute oxidative stress and proposed to be

mediated via a selective chaperone-mediated pathway [73]. Furthermore, the BAG3 siRNA

knockdown significantly hampers the autophagic activity exclusively in OxSR cells and therefore,

identifies BAG3 as one key positive autophagy modulator in OxSR cells (Figure 4). These data

underline a strong role of BAG3 in boosting autophagy in OxSR cells but shows also for the first

time that the expression switch from BAG1 to BAG3 and the functional switch from proteasomal

pathway to BAG3-mediated macroautophagy can be of permanent nature under stable adaptation

to oxidative stress as observed before during acute redox stress and aging [21], [58]. It is

important to note here that neither knock-down of BAG3 via siRNA nor a general autophagy

18 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

inhibition with bafilomycin A1 reversed the resistance phenotype (data not shown) strongly

arguing that during long-term adaptation to redox stress actually a combination of different

pathways may ensure oxidative stress resistance. This is strongly supported by our full proteome

analysis as well as by previously identified factors that partially contribute to oxidative stress

resistance such as NF-B, sphingolipids and increased levels of antioxidant enzymes [26], [27],

[28]. Indeed, employing MS-based global proteome analysis comparing OxSR and HT22-WT cells

several proteins were identified to be differentially expressed and significant changes in several

key pathways in addition to autophagy were revealed e.g. alteration in the ER stress response,

fatty acid metabolism, glycolysis, oxidative stress response and survival of neurons, mitochondrial

pathways and disorders. This argues towards the involvement of a wide array of changes involved

in redox stress adaptation (Figure 5) and demonstrates also the plasticity and adaptability of

various cellular pathways during chronic redox stress.

In summary we propose that upregulated autophagy in OxSR cells follows an mTOR-

independent pathway. BECN1/PI3KC3 and ATG9B, critical proteins for autophagy induction and

downstream execution respectively are highly upregulated during adaptation to oxidative stress.

Moreover, the HSP70-cochaperone BAG3 is not only increased in its expression, but it is also

active to participate in the upregulated selective macroautophagy in OxSR cells and also directly

impacts on the lysosomal rearrangement. OxSR cells described here in detail may be a useful

model to study these adaptive pathways and may also represent a tool to decipher further factors

and interacting pathways able to boost autophagic flux in neuronal cells. Altogether analyzing the

process of adaptation to chronic redox stress reveals potential novel therapeutic targets mediating

a robust adaptability to long-term oxidative stress conditions and a disturbed proteostasis as

important hallmarks of neurodegenerative disease and aging.

Conflict of interest

The authors declare no conflict of interest.

19 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Acknowledgment This study was supported by grants of the CRC1177 of the Deutsche

Forschungsgemeinschaft (DFG) and the Peter Beate Heller Foundation to CB and Foundation

Fighting Blindness (FFB) (PPA-0717-0719-RAD) (to UW). Caroline Manicam is supported by a

grant from the DFG (MA 8006/1-1). The authors are grateful to Milena Rossmanith and Katharina

Träger for their assistance with sample preparation for mass spectrometry analyses and to

Andreas Kern, Jana Schepers and Albrecht Clement for critical reading.

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Figure 1: OxSR cells show higher autophagic activity.

(A) Ultrastructure analysis of HT22-WT and OxSR cells by TEM. OxSR cells clearly showed

increased number and size of highly electron dense vacuolar autophagic vesicles at different

stages of maturity (representative images are shown). Autophagosomes are indicated by A,

autolysosomes by AL, nucleus by N and mitochondria by M.

(B) Protein extracts from HT22-WT and OxSR cells have been taken after 6 h of BafA1 (8 µM)

treatment and expression of the indicated proteins was detected by Western blotting.

(C, D) The autophagic flux was measured after densitometric analysis. Therefore, tubulin

normalized LC3B-II and P62 levels in the absence of the lysosomal inhibitor were subtracted from

corresponding levels obtained in the presence of BafA1. Tubulin (TUB) is used as loading control.

Values represent mean ± S.E.M., n=3, **p<0.01 and control HT22-WT cells were set to 100%.

(E) HT22-WT and OxSR cells were immunohistochemically stained against the LC3B and

Cathepsin D (CTSD). Scale bar: 10 µm. Pictures were taken by confocal microscopy.

Figure 2: Adaptation to oxidative stress enhances expression of Beclin1, WIPI1, PI3KC3

and RAB18

(A) Scheme displays major regulators of canonical autophagy.

(B) Protein extracts from untreated HT22-WT and OxSR cells were used to perform Western blot

analysis for detection of indicated proteins.

(C, D, E, F, G) The diagrams display the indicated protein levels after normalization to

corresponding tubulin. Values represent mean ± S.E.M., n=3 to 5, *p<0.05, **p<0.01, *** p<0.001

and ns. for no significant statistical difference. Control HT22-WT cells were set to 100%.

(H, I) OxSR cells were incubated simultaneously with 10 µM Rapamycin (RAPA) and 8 µM of

BafA1 for 4 h and expression of the indicated proteins was detected by Western blotting. The

autophagic flux was measured after densitometry analysis with LC3B-II levels normalized to

29 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

tubulin. Values represent mean ± S.E.M., n=4, *p<0.05 and autophagic flux of untreated OxSR

cells were set as control 100%.

Table 1: Autophagy associated gene expression profiling of stress-resistant OxSR cells.

Total RNA from HT22-WT and OxSR cells was characterized by using the mouse Autophagy

Primer Library 1 (MATPL-1) and relative fold change in gene expression profile was analyzed by

comparing with HT22-WT cells as control. Green numbers indicate an upregulation greater than

1.5-fold, red numbers indicate a downregulation lower than 0.6-fold. Values represent mean ±

S.E.M., n=3, *p<0.05, **p<0.01, *** p<0.001 and NS for no significant statistical difference.

Figure 3: OxSR cells overcome proteotoxic stress more effectively than HT22-WT cells and

show an altered BAG1/BAG3 expression.

(A, B) protein extracts from untreated and canavanine- (CV-) treated samples of HT22-WT and

OxSR cells were analyzed by Western blot for indicated proteins. Bar graphs represent changes

in polyubiquitinated protein levels between untreated control and treated samples obtained by

densitometric analysis after normalized to tubulin. Values represent mean ± S.E.M., n=3, **p<0.01

and NS for no significant statistical difference. Polyubiquitinated proteins in untreated cells were

set as control 100%.

(C) Protein extracts from untreated HT22-WT and OxSR cells were subjected to Western blot

analysis for BAG1 and BAG3 expression; tubulin was used as loading control.

(D, E) Quantification of the expression of BAG1L and BAG3 by densitometry analysis and

normalization to tubulin. Values represent mean ± S.E.M., n=3 to 4, **p<0.01 and control HT22

cells were set to 100%.

(F) OxSR cells were treated with MG132 and immunocytochemically analyzed for BAG3 positive

aggresomes surrounded with cage like vimentin structure by confocal microscope. Scale bar: 10

µm.

30 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Figure 4: BAG3 is required for autophagic activity in OxSR lines and BAG3 overexpression

promotes autophagy in HT22-WT cells.

(A, B, C, D) HT22-WT cells transfected for 48 h with empty vector (P-Flag-N1) or BAG3

overexpression vector (P-Flag-BAG3) and treated with vehicle or with BafA1 for 6 hr before the

cell lysis. Protein extracts were analyzed via Western blotting for indicated proteins. Quantification

of LAMP2, BAG3 expression and autophagic flux were prepared by densitometric analysis after

normalization of protein levels to tubulin. Values represent mean ± S.E.M., n=4, **p<0.01 and ***

p<0.001. Expression in empty vector transfected cells were set to 100%.

(E, F, G) OxSR cells were transfected with nonsense siRNA (NS) and BAG3 siRNA (siBAG3) for

48 h. Protein extracts from vehicle or BafA1-treated cells were subjected to Western blot analysis.

Quantification of BAG3 expression and autophagic flux were prepared after densitometric

analysis and normalization to tubulin. Values represent mean ± S.E.M., n=3, **p<0.01 and ***

p<0.001. Expression in nonsense siRNA transfected cells were set to 100%.

(H) Quantitative bar graph shows number of cells with distinct acidic vacuoles found with

LysoTracker staining in untreated HT22-WT, HT22 empty vector transfected (HT22-WTeV), HT22

overexpressing BAG3 (HT22-WTBAG3) and OxSR cells. Values represent mean ± S.E.M., n=4

with 3 to 8 images of different microscopic fields was counted in each day for every experimental

condition, **p<0.01.

(I) Representative confocal images of LysoTracker red staining (LT) in untreated HT22-WT,

HT22-WTeV, HT22-WTBAG3 and OxSR cells are shown indicating the changes in lysosomal

phenotype. Arrows indicate cells containing distinct acidic vacuolar structure. DAPI (blue) was

used to stain DNA. Scale bars: 10 µm.

31 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Figure 5: Comparative proteomics analyses of the HT22-WT and OxSR cells.

(A) Hierarchical clustering of the 176 differentially expressed proteins depicted as a heat map

distinguishes two major clusters of proteins. The first cluster represents significantly down-

regulated (green) and the second cluster up-regulated (red) proteins in OxSR cells compared to

HT22-WT. R1 to R3 represent the biological replicates.

(B) Pie chart displays cellular functions and abundance of proteins which are differentially

expressed in OxSR cells compared to HT22-WT cells. The detailed list of proteins in each cellular

functional group is provided with Supplementary file S4D “Proteomics data” where arrows depict

the up- and down-regulation of the proteins, respectively.

Supplementary figure S1: Results from cell proliferation assay, immunocytochemical

analysis of TFEB, expression of mitochondrial protein DLP1 and Proteasomal activity.

(A) Proliferation/growth rate of HT22-WT and OxSR cells were measured by MTT assay over nine

alternate days. Values represent mean ± S.E.M., n=3, *** p<0.001

(B) Immunocytochemical analysis reveals a distinct nuclear translocation of TFEB in OxSR cells

compared to cytosolic distribution in HT22-WT under basal condition. HT22-WT cells are treated

with 10 µM Rapamycin for 2h to induce TFEB nuclear translocation as a positive control

experiment (HT22-WT+RAPA). Scale bars: 10 μm. Images were acquired by confocal

microscopy.

(C) Protein extracts from untreated samples of HT22-WT and OxSR cells were analyzed by

Western blotting for DLP1 expression. Tubulin was used as loading control.

(D) Bar graph shows changes in DLP1 levels obtained by densitometry analysis and normalization

to Tubulin. Values represent mean ± S.E.M., n=3, *** p<0.001. Control HT22-WT cells were set

to 100%.

32 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

(E) Proteasomal activity of HT22-WT and OxSR is measured using fluorescence signal by release

of AMC from proteasomal substrate Suc-LLVY-AMC by proteasomal enzyme activity. Values

represent mean ± S.E.M., n=5, *** p<0.001. Control HT22-WT cells were set to 100%.

Supplementary figure S2: PPI Networks of the significantly differentially expressed

proteins in OxSR cells.

The protein-protein interaction (PPI) network of the differentially expressed proteins analyzed by

IPA analysis demonstrated the involvement of three major protein clusters in autophagy,

mitochondrial disorders and oxidative stress-related processes. Red and green colors of the

molecules indicate up- and down-regulation of the proteins, respectively, and different intensities

correspond to the magnitude of expression change of the individual proteins. The proteins were

further distinguished according to their cellular localization and molecular functional classes with

different shapes representing enzymes, ion channels, peptidases, transmembrane receptors etc.

The detailed result is provided in Supplementary file S4E “Proteomics data”.

Supplementary figure S3: Proteomics methods.

Details of the materials, methods, statistics and software employed for proteomics analysis is

described here.

Supplementary figure S4: Proteomics data.

(A) Complete list of all the proteins identified in proteome analysis of HT22-WT and OxSR cells

employing MaxQuant.

(B) The degree of variances in the proteome between the biological replicates and groups

assessed by Pearson's correlation analysis

(C) List of the differentially expressed proteins in OxSR cells compared to HT22-WT cell line.

33 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

(D) The detailed list of differentially expressed proteins in OxSR cells associated with each group

of different cellular functions as indicated in Figure 5B. Upregulation and downregulation of

expression in indicated by up (↑) and down (↓) arrows respectively.

(E) Complete Protein-protein interactions network of the differentially expressed proteins in OxSR

cells compared to HT22-WT cells as shown in Figure S2.

(F) MaxQuant Parameters.

34 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Table 1: Autophagy associated gene expression profile of stress resistant OxSR cells.

HT22-WT vs. OxSR Gene Fold Significant Name Change level ATG1/ULK Ulk2 0.4 * complex Ambra1 2.4 NS Other ATG Atg10 2.3 *** Atg12 1.6 *** Atg16L2 0.6 * Atg4A 3.3 *** Atg4B 1.5 NS Atg4C 2.6 NS Atg4D 2.6 NS Atg5 2.3 **** Atg7 2.0 NS Atg9A 1.9 NS Atg9B 36.6 * Wipi1 1.7 *** Gabarapl1 1.9 NS Gabarapl2 1.6 ** Map1LC3A 0.2 *** BECN1/PI3KC3 Bcl2L1 5.4 NS complex Becn1 2.1 ** PiK3c3 1.7 NS Autophagy Sqstm1 3.3 *** adaptor mTOR complex Raptor 2.2 NS Rictor 1.8 NS AKT1s1 1.5 ** Lysosome Dram 1.3 NS associated Lamp1 3.4 ** Lamp3 2.3 NS others Bire5 1.5 * Bnip3 6.1 *** Ddit3 2.1 ** Eif4ebp1 2.1 *** Eif4g1 1.9 ** Fkbp15 0.5 NS Gfi 1 b 3.2 NS Gpsm1 1.9 * Letm1 3.3 *** Letm2 3.8 *** Rasd1 2.0 NS Sec16A 2.3 NS Sec16B 1.6 NS Sec23A 2.0 * Sec23B 2.2 ** Sh3glb1 2.0 ** Sh3glb2 3.4 ** Snx30 1.9 NS Tpr 1.6 * Tpr53 0.5 * Ulk3 1.8 NS

bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Supplementary figure S4: Proteomics data.

(A) Complete list of all the proteins identified in proteome analysis of HT22-WT and OxSR

cells employing MaxQuant.

(B) The degree of variances in the proteome between the biological replicates and groups

assessed by Pearson's correlation analysis

(C) List of the differentially expressed proteins in OxSR cells compared to HT22-WT cell line.

(D) The detailed list of differentially expressed proteins in OxSR cells associated with each

group of different cellular functions as indicated in Figure 5B. Upregulation and

downregulation of expression in indicated by up (↑ ) and down ( ↓) arrows respectively.

(E) Complete Protein-protein interactions network of the differentially expressed proteins in

OxSR cells compared to HT22-WT cells as shown in Figure S2.

(F) MaxQuant Parameters. bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Supplementary file 4A : Complete list of all the proteins identified in proteome analysis of HT22-WT and OxSR cells employing MaxQuant

Razor + Mol. Majority Sequence Sequence LFQ intensity LFQ intensity LFQ intensity LFQ intensity LFQ intensity LFQ intensity Protein names Gene names unique weight Score protein IDs coverage [%] length HT22-WT R1 HT22-WT R2 HT22-WT R3 OxSR R1 OxSR R2 OxSR R3 peptides [kDa] 1 P62806 Histone H4 HIST1H4A 15 59.2 11.4 103 176 1.0E+10 1.2E+10 1.3E+10 8.0E+09 7.1E+09 6.6E+09 2 Q64523 Histone H2A type 2-C HIST2H2AC 8 58.1 14.0 129 123 9.0E+09 4.9E+09 6.9E+09 4.5E+09 6.4E+09 8.5E+09 3 P20152 Vimentin VIM 51 85.0 53.7 466 323 5.8E+09 4.7E+09 3.2E+09 6.0E+09 6.9E+09 5.9E+09 4 P63261 Actin, cytoplasmic 2 ACTG1 28 93.1 41.8 375 323 4.9E+09 5.6E+09 5.1E+09 3.3E+09 2.9E+09 2.9E+09 5 Q71DI3 Histone H3.2 HIST2H3A 7 46.3 15.4 136 49 4.8E+09 3.7E+09 6.0E+09 2.5E+09 1.5E+09 3.5E+09 6 Q99879 Histone H2B type 1-M HIST1H2BM 9 58.7 14.0 126 146 4.4E+09 2.9E+09 3.8E+09 2.8E+09 3.4E+09 2.8E+09 7 P15864 Histone H1.2 HIST1H1C 12 41.5 21.3 212 48 1.2E+09 1.1E+09 1.2E+09 5.7E+08 6.8E+08 6.4E+08 8 P48678 Prelamin-A/C LMNA 50 68.3 74.2 665 323 1.1E+09 1.1E+09 8.9E+08 8.1E+08 6.9E+08 8.7E+08 9 P16045 Galectin-1 LGALS1 10 94.1 14.9 135 232 1.1E+09 1.3E+09 1.9E+09 2.3E+09 1.1E+09 1.2E+09 10 P48962 ADP/ATP translocase 1 SLC25A4 16 49.3 32.9 298 162 8.6E+08 7.5E+08 1.0E+09 8.1E+08 1.2E+09 1.2E+09 11 Q03265 ATP synthase subunit alpha, mitochondrial ATP5A1 28 56.4 59.8 553 323 8.6E+08 8.1E+08 5.2E+08 7.8E+08 7.1E+08 6.6E+08 12 Q64433 10 kDa heat shock protein, mitochondrial HSPE1 9 73.5 11.0 102 66 8.0E+08 6.8E+08 1.0E+09 1.2E+09 8.8E+08 7.7E+08 13 Q8BFZ3 Beta-actin-like protein 2 ACTBL2 2 38.6 42.0 376 5 7.6E+08 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 14 Q14520 Hyaluronan-binding protein 2 HABP2 1 3.4 62.7 560 -2 7.4E+08 0.0E+00 4.9E+08 7.6E+08 5.8E+08 0.0E+00 15 P63038 60 kDa heat shock protein, mitochondrial HSPD1 44 77.1 61.0 573 323 6.9E+08 6.8E+08 7.1E+08 9.7E+08 8.9E+08 1.3E+09 Voltage-dependent anion-selective channel 16 Q60932 VDAC1 14 69.6 32.4 296 323 5.5E+08 4.8E+08 5.5E+08 6.2E+08 3.6E+08 3.9E+08 protein 1 17 P63017 Heat shock cognate 71 kDa protein HSPA8 34 62.7 70.9 646 323 5.1E+08 5.5E+08 6.0E+08 9.0E+08 5.9E+08 6.3E+08 18 P62987 Ubiquitin-60S ribosomal protein L40 UBA52 4 36.7 14.7 128 84 5.0E+08 4.6E+08 6.6E+08 5.6E+08 3.7E+08 4.1E+08 19 P08249 Malate dehydrogenase, mitochondrial MDH2 19 67.8 35.6 338 307 4.9E+08 4.0E+08 6.2E+08 1.3E+09 1.2E+09 1.5E+09 20 P56480 ATP synthase subunit beta, mitochondrial ATP5B 28 74.7 56.3 529 323 4.9E+08 4.9E+08 6.5E+08 6.5E+08 5.4E+08 5.1E+08 21 P04264 Keratin, type II cytoskeletal 1 KRT1 24 31.2 66.0 644 317 4.9E+08 5.4E+08 1.8E+08 1.5E+08 3.4E+08 1.3E+08 22 Q9DCN2 NADH-cytochrome b5 reductase 3 CYB5R3 13 51.2 34.1 301 81 4.7E+08 3.7E+08 3.9E+08 2.6E+08 2.3E+08 2.5E+08 23 Q9QXS1 Plectin PLEC 187 46.2 534.2 4691 323 4.6E+08 3.9E+08 5.4E+08 4.6E+08 3.1E+08 4.4E+08 24 P38647 Stress-70 protein, mitochondrial HSPA9 27 47.6 73.5 679 323 4.6E+08 4.9E+08 4.9E+08 6.0E+08 3.8E+08 4.2E+08 Heterogeneous nuclear ribonucleoproteins 25 P22626 HNRNPA2B1 19 59.2 37.4 353 219 4.6E+08 4.0E+08 4.0E+08 2.5E+08 3.2E+08 3.6E+08 A2/B1 26 P10126 Elongation factor 1-alpha 1 EEF1A1 14 41.3 50.1 462 107 4.5E+08 3.6E+08 2.5E+08 4.5E+08 5.5E+08 4.6E+08 27 P43276 Histone H1.5 HIST1H1B 9 38.6 22.6 223 49 4.3E+08 4.4E+08 4.7E+08 1.9E+08 2.1E+08 2.3E+08 28 P51881 ADP/ATP translocase 2 SLC25A5 8 53.4 32.9 298 49 4.2E+08 3.7E+08 4.2E+08 2.6E+08 4.0E+08 3.9E+08 29 P07091 Protein S100-A4 S100A4 7 51.5 11.7 101 84 4.0E+08 3.7E+08 3.5E+08 4.9E+08 5.7E+08 7.0E+08 30 P68363 Tubulin alpha-1B chain TUBA1B 20 64.5 50.2 451 323 3.8E+08 4.1E+08 4.3E+08 3.7E+08 3.4E+08 3.0E+08 31 P99024 Tubulin beta-5 chain TUBB5 21 59.9 49.7 444 323 3.7E+08 3.3E+08 3.0E+08 2.7E+08 2.6E+08 2.6E+08 32 P07356 Annexin A2 ANXA2 19 66.1 38.7 339 323 3.7E+08 3.7E+08 3.9E+08 3.4E+08 3.1E+08 3.0E+08 33 P62702 40S ribosomal protein S4, X isoform RPS4X 15 47.1 29.6 263 113 3.6E+08 3.6E+08 2.8E+08 2.3E+08 2.9E+08 2.5E+08 34 P67778 Prohibitin PHB 16 81.6 29.8 272 250 3.5E+08 3.0E+08 3.4E+08 2.9E+08 2.6E+08 2.9E+08 35 P20029 78 kDa glucose-regulated protein HSPA5 32 51.3 72.4 655 323 3.4E+08 3.7E+08 6.7E+08 5.7E+08 3.8E+08 4.4E+08 36 Q71UI9 Histone H2A.V H2AFV 4 53.9 13.5 128 91 3.3E+08 3.6E+08 3.3E+08 3.0E+08 3.9E+08 3.7E+08 37 Q99623 Prohibitin-2 PHB2 12 46.2 33.3 299 205 3.2E+08 2.4E+08 2.8E+08 2.1E+08 1.5E+08 1.8E+08 38 P51150 Ras-related protein Rab-7a RAB7A 14 72.5 23.5 207 301 3.2E+08 2.8E+08 3.2E+08 1.5E+08 1.9E+08 1.9E+08 39 P11499 Heat shock protein HSP 90-beta HSP90AB1 36 50.1 83.3 724 323 3.1E+08 3.6E+08 4.0E+08 3.6E+08 3.6E+08 4.6E+08 40 P25444 40S ribosomal protein S2 RPS2 14 49.1 31.2 293 131 3.0E+08 3.1E+08 2.5E+08 1.9E+08 2.2E+08 2.1E+08 41 P35564 Calnexin CANX 28 54.0 67.3 591 300 2.9E+08 3.9E+08 4.8E+08 6.8E+08 5.4E+08 5.8E+08 42 C0HKE9 Histone H2A type 1-H HIST1H2AH 2 35.4 14.1 130 37 2.7E+08 7.1E+07 2.2E+08 0.0E+00 0.0E+00 6.9E+08 43 Q8BMK4 Cytoskeleton-associated protein 4 CKAP4 32 58.8 63.7 575 323 2.5E+08 1.6E+08 2.7E+08 1.8E+08 3.0E+08 3.7E+08 44 Q9Z110 Delta-1-pyrroline-5-carboxylate synthase ALDH18A1 30 45.9 87.3 795 310 2.4E+08 1.8E+08 1.9E+08 7.6E+07 4.1E+07 3.8E+07 Dolichyl-diphosphooligosaccharide--protein 45 Q91YQ5 RPN1 26 52.0 68.5 608 195 2.4E+08 2.3E+08 2.2E+08 1.7E+08 1.6E+08 2.1E+08 glycosyltransferase subunit 1 46 P62242 40S ribosomal protein S8 RPS8 10 51.0 24.2 208 184 2.4E+08 2.8E+08 2.0E+08 1.4E+08 1.9E+08 2.1E+08 47 P09103 Protein disulfide-isomerase P4HB 27 57.0 57.1 509 290 2.4E+08 2.1E+08 4.2E+08 2.7E+08 2.1E+08 2.1E+08 48 P19324 Serpin H1 SERPINH1 18 61.2 46.5 417 323 2.3E+08 1.7E+08 3.2E+08 6.7E+07 6.6E+07 7.9E+07 49 P49312 Heterogeneous nuclear ribonucleoprotein A1 HNRNPA1 15 51.2 34.2 320 227 2.3E+08 2.9E+08 2.1E+08 1.6E+08 1.5E+08 1.4E+08 50 Q922Q8 Leucine-rich repeat-containing protein 59 LRRC59 12 49.8 34.9 307 226 2.2E+08 2.3E+08 2.6E+08 3.4E+08 3.5E+08 3.1E+08 51 P51991 Heterogeneous nuclear ribonucleoprotein A3 HNRNPA3 16 32.3 39.6 378 188 2.2E+08 2.0E+08 2.1E+08 1.5E+08 2.0E+08 9.8E+07 52 P62908 40S ribosomal protein S3 RPS3 13 53.9 26.7 243 101 2.2E+08 2.4E+08 2.2E+08 1.7E+08 1.9E+08 1.9E+08 53 Q8VEM8 Phosphate carrier protein, mitochondrial SLC25A3 12 38.7 39.6 357 182 2.1E+08 2.2E+08 3.0E+08 2.6E+08 4.6E+08 5.9E+08 54 P09405 Nucleolin NCL 25 33.9 76.7 707 323 2.1E+08 2.7E+08 1.8E+08 1.0E+08 1.0E+08 1.7E+08 55 Q8VIJ6 Splicing factor, proline- and glutamine-rich SFPQ 17 28.9 75.4 699 166 2.0E+08 1.8E+08 1.8E+08 1.4E+08 1.2E+08 1.2E+08 Voltage-dependent anion-selective channel 56 Q60930 VDAC2 9 41.7 31.7 295 142 1.7E+08 1.4E+08 1.4E+08 3.1E+08 3.4E+08 3.6E+08 protein 2 57 P62906 60S ribosomal protein L10a RPL10A 9 48.4 24.8 217 75 1.7E+08 2.1E+08 1.5E+08 1.1E+08 1.4E+08 1.6E+08 58 Q61937 Nucleophosmin NPM1 10 36.6 32.6 292 115 1.7E+08 2.0E+08 1.2E+08 9.4E+07 1.1E+08 1.1E+08 59 P12970 60S ribosomal protein L7a RPL7A 9 28.2 30.0 266 72 1.7E+08 2.2E+08 1.6E+08 1.2E+08 1.4E+08 1.4E+08 60 P14211 Calreticulin CALR 24 73.6 48.0 416 209 1.6E+08 1.9E+08 2.5E+08 3.1E+08 2.5E+08 2.8E+08 61 P27773 Protein disulfide-isomerase A3 PDIA3 28 59.2 56.7 505 300 1.5E+08 1.8E+08 2.7E+08 3.2E+08 3.9E+08 4.7E+08 62 Q99P72 Reticulon-4 RTN4 12 16.4 126.6 1162 153 1.5E+08 1.4E+08 2.1E+08 1.8E+08 2.5E+08 2.6E+08 63 P17225 Polypyrimidine tract-binding protein 1 PTBP1 12 36.4 56.5 527 261 1.5E+08 1.2E+08 7.5E+07 6.1E+07 7.0E+07 5.0E+07 64 Q9CZN7 Serine hydroxymethyltransferase SHMT2 21 57.9 55.8 504 323 1.5E+08 1.4E+08 2.2E+08 1.1E+08 1.0E+08 8.7E+07 65 P18760 Cofilin-1 CFL1 11 64.5 18.6 166 153 1.5E+08 1.7E+08 1.9E+08 2.6E+08 1.6E+08 2.4E+08 66 P97351 40S ribosomal protein S3a RPS3A 9 31.1 29.9 264 51 1.5E+08 1.6E+08 1.3E+08 8.3E+07 1.1E+08 9.6E+07 67 P43277 Histone H1.3 HIST1H1D 2 35.7 22.1 221 9 1.5E+08 1.4E+08 1.7E+08 5.8E+07 8.2E+07 8.0E+07 68 P14148 60S ribosomal protein L7 RPL7 10 40.7 31.4 270 47 1.5E+08 1.7E+08 1.5E+08 9.4E+07 1.1E+08 1.1E+08 69 Q6ZWN5 40S ribosomal protein S9 RPS9 11 41.2 22.6 194 24 1.5E+08 1.8E+08 1.4E+08 9.2E+07 1.4E+08 1.2E+08 70 P68033 Actin, alpha cardiac muscle 1 ACTC1 2 39.5 42.0 377 25 1.5E+08 1.5E+08 1.1E+08 1.9E+08 9.2E+07 3.8E+07 71 Q9DB20 ATP synthase subunit O, mitochondrial ATP5O 9 57.7 23.4 213 99 1.5E+08 1.3E+08 1.1E+08 1.5E+08 2.4E+08 2.6E+08 72 Q99KI0 Aconitate hydratase, mitochondrial ACO2 31 47.4 85.5 780 278 1.5E+08 1.2E+08 1.5E+08 1.0E+08 1.3E+08 1.7E+08 73 P10852 4F2 cell-surface antigen heavy chain SLC3A2 15 39.0 58.3 526 107 1.4E+08 1.4E+08 1.4E+08 5.9E+07 5.7E+07 5.7E+07 74 P43274 Histone H1.4 HIST1H1E 2 32.0 22.0 219 14 1.4E+08 1.8E+08 1.7E+08 1.0E+08 1.4E+08 1.1E+08 75 Q8VEK3 Heterogeneous nuclear ribonucleoprotein U HNRNPU 24 32.5 87.9 800 209 1.4E+08 1.4E+08 1.1E+08 1.0E+08 9.3E+07 1.0E+08 76 Q9JJI8 60S ribosomal protein L38 RPL38 5 50.0 8.2 70 74 1.4E+08 1.6E+08 1.2E+08 7.9E+07 1.1E+08 1.2E+08 77 Q8VDD5 Myosin-9 MYH9 50 31.6 226.4 1960 323 1.4E+08 1.4E+08 9.8E+07 7.9E+07 7.9E+07 8.0E+07 78 P35700 Peroxiredoxin-1 PRDX1 12 68.8 22.2 199 53 1.4E+08 1.5E+08 2.0E+08 3.3E+08 2.4E+08 2.8E+08 79 Q68FD5 Clathrin heavy chain 1 CLTC 52 39.4 191.6 1675 323 1.4E+08 1.2E+08 1.2E+08 1.6E+08 2.0E+08 1.9E+08 80 Q9CPQ8 ATP synthase subunit g, mitochondrial ATP5L 4 41.7 11.4 103 13 1.3E+08 1.2E+08 1.2E+08 1.3E+08 1.4E+08 1.5E+08 Heterogeneous nuclear ribonucleoproteins 81 Q9Z204 HNRNPC 10 28.1 34.4 313 72 1.3E+08 9.3E+07 9.5E+07 9.4E+07 5.2E+07 4.8E+07 C1/C2 82 P62827 GTP-binding nuclear protein Ran RAN 9 44.9 24.4 216 50 1.3E+08 1.5E+08 1.5E+08 1.6E+08 1.4E+08 1.3E+08 Voltage-dependent anion-selective channel 83 Q9Y277 VDAC3 8 38.2 30.7 283 158 1.3E+08 1.3E+08 1.5E+08 1.3E+08 1.3E+08 1.3E+08 protein 3 84 Q62425 Cytochrome c oxidase subunit NDUFA4 NDUFA4 6 47.6 9.3 82 28 1.3E+08 1.1E+08 1.0E+08 5.9E+07 8.6E+07 8.4E+07 85 Q9CZM2 60S ribosomal protein L15 RPL15 9 42.6 24.1 204 79 1.3E+08 1.5E+08 1.1E+08 8.9E+07 9.8E+07 1.1E+08 86 P05202 Aspartate aminotransferase, mitochondrial GOT2 19 52.8 47.4 430 204 1.2E+08 1.1E+08 1.4E+08 1.6E+08 1.6E+08 1.9E+08 ATP synthase F(0) complex subunit B1, 87 Q9CQQ7 ATP5F1 10 43.0 28.9 256 101 1.2E+08 1.0E+08 1.0E+08 5.7E+07 1.6E+08 1.5E+08 mitochondrial 88 O70133 ATP-dependent RNA helicase A DHX9 27 21.4 149.5 1380 204 1.2E+08 1.4E+08 1.1E+08 1.3E+08 1.1E+08 1.1E+08 89 Q9DCX2 ATP synthase subunit d, mitochondrial ATP5H 13 76.4 18.7 161 166 1.2E+08 1.1E+08 1.2E+08 1.9E+08 1.3E+08 1.5E+08 90 Q91VR2 ATP synthase subunit gamma, mitochondrial ATP5C1 8 37.6 32.9 298 60 1.2E+08 8.6E+07 1.2E+08 1.5E+08 1.7E+08 1.8E+08 91 P61979 Heterogeneous nuclear ribonucleoprotein K HNRNPK 13 33.5 51.0 463 145 1.2E+08 8.8E+07 7.8E+07 5.3E+07 5.7E+07 4.3E+07 92 P16110 Galectin-3 LGALS3 5 24.2 27.5 264 51 1.2E+08 1.2E+08 9.7E+07 2.2E+08 2.4E+08 3.0E+08 93 P62821 Ras-related protein Rab-1A RAB1A 6 44.9 22.7 205 97 1.2E+08 9.9E+07 1.2E+08 9.3E+07 1.1E+08 1.0E+08 94 P52480 Pyruvate kinase PKM PKM 26 53.5 57.8 531 323 1.1E+08 1.2E+08 1.4E+08 2.9E+08 2.0E+08 2.5E+08 95 P35980 60S ribosomal protein L18 RPL18 7 41.0 21.6 188 81 1.1E+08 1.4E+08 1.2E+08 1.3E+08 1.2E+08 1.0E+08 96 P16858 Glyceraldehyde-3-phosphate dehydrogenase GAPDH 9 39.6 35.8 333 171 1.1E+08 1.1E+08 1.2E+08 2.6E+08 2.1E+08 2.2E+08 97 P61019 Ras-related protein Rab-2A RAB2A 11 58.5 23.5 212 237 1.1E+08 1.0E+08 1.2E+08 9.5E+07 1.1E+08 1.1E+08 98 P62082 40S ribosomal protein S7 RPS7 9 53.1 22.1 194 65 1.1E+08 1.2E+08 8.4E+07 1.3E+08 1.1E+08 1.6E+08 99 P19253 60S ribosomal protein L13a RPL13A 6 29.6 23.5 203 45 1.1E+08 1.2E+08 9.9E+07 8.1E+07 1.1E+08 1.2E+08 100 Q9CZU6 Citrate synthase, mitochondrial CS 11 24.6 51.7 464 70 1.1E+08 9.4E+07 1.4E+08 1.4E+08 1.3E+08 1.5E+08 101 P08113 Endoplasmin HSP90B1 41 50.1 92.5 802 323 1.1E+08 1.6E+08 3.4E+08 6.1E+08 4.4E+08 4.4E+08 102 P14869 60S acidic ribosomal protein P0 RPLP0 9 40.1 34.2 317 107 1.1E+08 1.6E+08 1.0E+08 1.2E+08 1.1E+08 1.1E+08 103 P62754 40S ribosomal protein S6 RPS6 6 29.7 28.7 249 94 1.1E+08 9.1E+07 7.7E+07 5.4E+07 7.8E+07 6.8E+07 104 P17182 Alpha-enolase ENO1 21 66.1 47.1 434 323 1.1E+08 1.8E+08 1.8E+08 3.8E+08 3.1E+08 3.5E+08 105 O08807 Peroxiredoxin-4 PRDX4 10 44.9 31.1 274 71 1.1E+08 1.1E+08 2.6E+08 2.4E+08 1.8E+08 2.3E+08 106 P35979 60S ribosomal protein L12 RPL12 6 54.5 17.8 165 196 1.1E+08 1.3E+08 1.0E+08 1.2E+08 1.2E+08 1.1E+08 107 P06151 L-lactate dehydrogenase A chain LDHA 11 36.4 36.5 332 104 1.1E+08 8.0E+07 1.1E+08 1.6E+08 7.6E+07 1.0E+08 108 P14733 Lamin-B1 LMNB1 16 32.1 66.8 588 261 1.1E+08 9.9E+07 1.2E+08 5.7E+07 4.7E+07 4.2E+07 109 Q06185 ATP synthase subunit e, mitochondrial ATP5I 4 52.1 8.2 71 37 1.1E+08 1.3E+08 9.4E+07 1.1E+08 1.4E+08 1.4E+08 110 Q9CR57 60S ribosomal protein L14 RPL14 5 25.8 23.6 217 48 1.0E+08 1.5E+08 9.2E+07 5.2E+07 6.0E+07 5.0E+07 111 O70503 Very-long-chain 3-oxoacyl-CoA reductase HSD17B12 12 50.6 34.7 312 132 1.0E+08 1.0E+08 1.1E+08 8.3E+07 1.2E+08 1.2E+08 112 P62281 40S ribosomal protein S11 RPS11 9 44.3 18.4 158 62 1.0E+08 1.2E+08 9.0E+07 9.4E+07 1.1E+08 1.0E+08 113 P56135 ATP synthase subunit f, mitochondrial ATP5J2 4 36.4 10.3 88 19 9.7E+07 9.3E+07 6.5E+07 7.0E+07 8.7E+07 8.5E+07 114 P14069 Protein S100-A6 S100A6 4 66.3 10.1 89 14 9.6E+07 1.1E+08 1.2E+08 1.1E+08 1.1E+08 1.2E+08 Dolichyl-diphosphooligosaccharide--protein 115 O54734 DDOST 14 47.2 49.0 441 187 9.6E+07 7.5E+07 6.9E+07 1.1E+08 9.0E+07 7.8E+07 glycosyltransferase 48 kDa subunit 116 P35279 Ras-related protein Rab-6A RAB6A 5 32.7 23.6 208 60 9.5E+07 9.1E+07 1.0E+08 7.5E+07 7.4E+07 7.0E+07 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

117 P12787 Cytochrome c oxidase subunit 5A, mitochondrial COX5A 8 59.6 16.1 146 50 9.4E+07 1.0E+08 1.9E+08 8.7E+07 8.0E+07 9.1E+07 118 P62270 40S ribosomal protein S18 RPS18 9 52.0 17.7 152 36 9.3E+07 1.1E+08 8.4E+07 1.1E+08 9.7E+07 1.1E+08 Isocitrate dehydrogenase [NADP], 119 P54071 IDH2 21 46.9 50.9 452 219 9.2E+07 8.1E+07 1.3E+08 8.9E+07 8.7E+07 7.6E+07 mitochondrial 120 P35278 Ras-related protein Rab-5C RAB5C 7 43.1 23.4 216 122 9.0E+07 6.8E+07 8.3E+07 7.7E+07 7.4E+07 8.9E+07 Supplementary file 4A : (continued) 121 P63101 14-3-3 protein zeta/delta YWHAZ 10 49.4 27.8 245 153 9.0E+07 1.1E+08 1.1E+08 8.0E+07 8.8E+07 8.2E+07 122 P43275 Histone H1.1 HIST1H1A 4 32.4 21.8 213 50 9.0E+07 9.0E+07 5.6E+07 5.0E+07 1.3E+08 1.2E+08 Succinate dehydrogenase [ubiquinone] 123 Q8K2B3 SDHA 16 33.0 72.6 664 144 9.0E+07 7.8E+07 6.6E+07 9.1E+07 7.0E+07 1.0E+08 flavoprotein subunit, mitochondrial Complement component 1 Q subcomponent- 124 O35658 C1QBP 9 54.7 31.0 278 146 9.0E+07 1.2E+08 1.4E+08 1.5E+08 1.5E+08 1.7E+08 binding protein, mitochondrial 125 P62249 40S ribosomal protein S16 RPS16 6 35.6 16.4 146 32 8.9E+07 8.8E+07 5.3E+07 7.9E+07 1.0E+08 6.5E+07 126 P49817 Caveolin-1 CAV1 6 46.6 20.5 178 39 8.9E+07 8.2E+07 1.0E+08 7.5E+07 6.9E+07 7.7E+07 127 P11087 Collagen alpha-1(I) chain COL1A1 22 24.5 138.0 1453 110 8.8E+07 6.9E+07 9.4E+07 0.0E+00 0.0E+00 0.0E+00 128 P17742 Peptidyl-prolyl cis-trans isomerase A PPIA 10 50.6 18.0 164 184 8.8E+07 1.3E+08 1.2E+08 1.4E+08 9.0E+07 1.3E+08 129 Q8CAQ8 MICOS complex subunit Mic60 IMMT 17 30.9 83.9 757 148 8.8E+07 5.9E+07 5.3E+07 5.7E+07 2.6E+07 4.6E+07 130 Q61656 Probable ATP-dependent RNA helicase DDX5 DDX5 12 23.5 69.3 614 47 8.7E+07 9.3E+07 4.6E+07 5.2E+07 4.6E+07 6.1E+07 131 P62245 40S ribosomal protein S15a RPS15A 7 60.8 14.8 130 36 8.7E+07 1.6E+08 1.2E+08 1.3E+08 1.1E+08 9.2E+07 132 P60867 40S ribosomal protein S20 RPS20 2 19.3 13.4 119 22 8.6E+07 1.0E+08 9.6E+07 1.3E+08 9.5E+07 8.8E+07 Cytochrome b-c1 complex subunit 2, 133 Q9DB77 UQCRC2 17 60.5 48.2 453 152 8.6E+07 7.6E+07 8.4E+07 5.1E+07 4.6E+07 5.7E+07 mitochondrial 134 Q9D8E6 60S ribosomal protein L4 RPL4 15 37.0 47.2 419 63 8.5E+07 9.9E+07 7.2E+07 5.7E+07 8.4E+07 6.7E+07 135 P47911 60S ribosomal protein L6 RPL6 10 34.8 33.5 296 91 8.5E+07 9.6E+07 7.7E+07 1.1E+08 6.3E+07 9.6E+07 136 Q02543 60S ribosomal protein L18a RPL18A 7 39.2 20.8 176 36 8.5E+07 9.0E+07 8.3E+07 6.3E+07 7.3E+07 6.9E+07 137 Q69ZN7 Myoferlin MYOF 55 34.0 233.3 2048 215 8.4E+07 7.5E+07 7.3E+07 1.5E+08 1.4E+08 1.5E+08 138 P56391 Cytochrome c oxidase subunit 6B1 COX6B1 7 70.9 10.1 86 27 8.2E+07 8.2E+07 1.3E+08 7.3E+07 4.6E+07 7.6E+07 139 P00405 Cytochrome c oxidase subunit 2 MTCO2 5 27.8 26.0 227 44 8.2E+07 6.6E+07 9.0E+07 3.2E+07 2.9E+07 2.6E+07 140 P47955 60S acidic ribosomal protein P1 RPLP1 5 94.7 11.5 114 61 8.2E+07 1.0E+08 8.4E+07 1.2E+08 1.2E+08 1.2E+08 Succinyl-CoA:3-ketoacid coenzyme A 141 Q9D0K2 OXCT1 14 45.0 56.0 520 287 8.2E+07 5.6E+07 4.2E+07 6.4E+07 4.9E+07 5.7E+07 transferase 1, mitochondrial Guanine nucleotide-binding protein 142 P62874 GNB1 11 37.6 37.4 340 165 8.1E+07 6.6E+07 9.2E+07 8.0E+07 8.7E+07 9.1E+07 G(I)/G(S)/G(T) subunit beta-1 143 P84244 Histone H3.3 H3F3A 1 46.3 15.3 136 30 8.0E+07 3.3E+07 1.1E+08 2.9E+07 4.5E+07 7.6E+07 Vesicle-associated membrane protein- 144 Q9WV55 VAPA 5 20.9 27.9 249 43 7.9E+07 7.2E+07 7.4E+07 7.7E+07 7.6E+07 8.7E+07 associated protein A 145 P22087 rRNA 2-O-methyltransferase fibrillarin FBL 8 36.4 33.8 321 35 7.8E+07 8.7E+07 9.1E+07 7.4E+07 6.2E+07 6.9E+07 146 P57780 Alpha-actinin-4 ACTN4 30 40.2 105.0 912 323 7.7E+07 6.4E+07 7.4E+07 5.7E+07 5.6E+07 6.5E+07 Cytochrome c oxidase subunit 4 isoform 1, 147 P19783 COX4I1 5 31.4 19.5 169 47 7.6E+07 8.7E+07 8.8E+07 8.1E+07 7.6E+07 9.2E+07 mitochondrial 148 O54962 Barrier-to-autointegration factor BANF1 7 60.7 10.1 89 38 7.6E+07 1.2E+08 1.4E+08 2.1E+08 1.5E+08 1.6E+08 149 P62830 60S ribosomal protein L23 RPL23 6 55.7 14.9 140 49 7.5E+07 7.1E+07 7.0E+07 4.0E+07 5.8E+07 7.7E+07 150 Q9CXW4 60S ribosomal protein L11 RPL11 6 35.4 20.3 178 61 7.4E+07 7.5E+07 6.9E+07 6.2E+07 7.8E+07 6.9E+07 151 P58252 Elongation factor 2 EEF2 28 41.6 95.3 858 316 7.4E+07 7.8E+07 7.5E+07 1.3E+08 1.1E+08 1.0E+08 152 P47963 60S ribosomal protein L13 RPL13 5 25.6 24.3 211 23 7.3E+07 9.7E+07 6.1E+07 5.6E+07 4.4E+07 1.3E+07 153 Q8BP67 60S ribosomal protein L24 RPL24 5 30.6 17.8 157 31 7.2E+07 8.6E+07 6.7E+07 2.7E+07 4.2E+07 3.3E+07 154 Q64133 Amine oxidase [flavin-containing] A MAOA 13 35.4 59.6 526 115 7.2E+07 6.1E+07 4.7E+07 5.9E+07 6.1E+07 5.2E+07 155 Q9CX86 Heterogeneous nuclear ribonucleoprotein A0 HNRNPA0 4 19.0 30.5 305 62 7.1E+07 7.1E+07 5.3E+07 4.1E+07 4.4E+07 3.2E+07 156 P29758 Ornithine aminotransferase, mitochondrial OAT 9 28.5 48.4 439 192 7.1E+07 5.1E+07 4.5E+07 2.5E+07 2.5E+07 2.7E+07 157 P51410 60S ribosomal protein L9 RPL9 7 57.8 21.9 192 68 7.1E+07 8.3E+07 6.9E+07 6.6E+07 4.5E+07 4.6E+07 Transmembrane emp24 domain-containing 158 Q9D1D4 TMED10 6 35.2 24.9 219 77 7.1E+07 6.2E+07 8.0E+07 7.2E+07 6.9E+07 7.6E+07 protein 10 Up-regulated during skeletal muscle growth 159 Q78IK2 USMG5 3 44.8 6.4 58 73 7.0E+07 7.0E+07 5.4E+07 6.1E+07 8.0E+07 8.2E+07 protein 5 160 P10922 Histone H1.0 H1F0 5 27.3 20.9 194 21 6.8E+07 5.4E+07 6.8E+07 3.3E+07 4.3E+07 3.4E+07 161 P62751 60S ribosomal protein L23a RPL23A 8 37.2 17.7 156 49 6.7E+07 9.0E+07 6.5E+07 5.1E+07 6.6E+07 4.3E+07 162 P62855 40S ribosomal protein S26 RPS26 4 37.4 13.0 115 20 6.7E+07 6.6E+07 5.4E+07 3.8E+07 6.9E+07 7.2E+07 163 P62900 60S ribosomal protein L31 RPL31 4 33.6 14.5 125 38 6.5E+07 7.0E+07 6.2E+07 7.0E+07 8.2E+07 6.6E+07 164 Q62186 Translocon-associated protein subunit delta SSR4 3 23.3 18.9 172 42 6.4E+07 6.2E+07 7.2E+07 4.9E+07 4.3E+07 4.4E+07 165 O08756 3-hydroxyacyl-CoA dehydrogenase type-2 HSD17B10 8 50.6 27.4 261 177 6.4E+07 7.4E+07 6.9E+07 1.5E+08 1.2E+08 1.4E+08 Dolichyl-diphosphooligosaccharide--protein 166 P61804 DAD1 4 35.4 12.5 113 21 6.3E+07 5.9E+07 8.0E+07 5.4E+07 9.1E+07 6.7E+07 glycosyltransferase subunit DAD1 167 P61255 60S ribosomal protein L26 RPL26 5 23.4 17.3 145 10 6.3E+07 6.0E+07 6.1E+07 5.0E+07 4.5E+07 4.8E+07 Leucine-rich PPR motif-containing protein, 168 Q6PB66 LRPPRC 36 32.0 156.6 1392 174 6.3E+07 7.1E+07 7.2E+07 8.1E+07 1.1E+08 1.3E+08 mitochondrial 169 Q15907 Ras-related protein Rab-11B RAB11B 10 54.1 24.5 218 61 6.2E+07 4.9E+07 5.4E+07 1.0E+08 1.2E+08 1.3E+08 170 P63325 40S ribosomal protein S10 RPS10 4 32.1 18.9 165 26 6.2E+07 8.3E+07 3.8E+07 4.5E+07 6.6E+07 6.2E+07 171 P62301 40S ribosomal protein S13 RPS13 7 38.4 17.2 151 68 6.2E+07 6.9E+07 5.0E+07 5.8E+07 6.2E+07 4.6E+07 172 Q9CQS8 Protein transport protein Sec61 subunit beta SEC61B 3 37.5 10.0 96 8 6.2E+07 5.0E+07 6.8E+07 3.4E+07 3.0E+07 3.1E+07 Sterol-4-alpha-carboxylate 3-dehydrogenase, 173 Q9R1J0 NSDHL 8 32.6 40.7 362 102 6.1E+07 6.3E+07 6.7E+07 4.8E+07 3.5E+07 4.1E+07 decarboxylating 174 Q8K0C4 Lanosterol 14-alpha demethylase CYP51A1 13 35.0 56.8 503 268 6.1E+07 6.8E+07 8.2E+07 3.4E+07 5.7E+07 5.1E+07 Monofunctional C1-tetrahydrofolate synthase, 175 Q3V3R1 MTHFD1L 26 34.7 105.7 977 106 6.0E+07 4.8E+07 5.6E+07 4.4E+07 4.2E+07 4.2E+07 mitochondrial Non-POU domain-containing octamer-binding 176 Q15233 NONO 9 22.9 54.2 471 63 6.0E+07 4.8E+07 3.0E+07 2.4E+07 3.1E+07 2.6E+07 protein 177 P67984 60S ribosomal protein L22 RPL22 4 50.8 14.8 128 38 6.0E+07 8.1E+07 6.7E+07 8.1E+07 7.2E+07 6.9E+07 Guanine nucleotide-binding protein G(i) subunit 178 P08752 GNAI2 9 33.5 40.5 355 152 6.0E+07 6.2E+07 7.0E+07 5.0E+07 3.1E+07 4.5E+07 alpha-2 179 Q60605 Myosin light polypeptide 6 MYL6 7 48.3 16.9 151 42 5.9E+07 5.7E+07 5.3E+07 6.4E+07 5.6E+07 5.5E+07 180 Q9WTI7 Unconventional myosin-Ic MYO1C 25 34.3 121.9 1063 221 5.8E+07 5.7E+07 7.4E+07 6.9E+07 5.7E+07 5.2E+07 181 P17066 Heat shock 70 kDa protein 6 HSPA6 1 6.5 71.0 643 21 5.7E+07 5.2E+07 9.1E+07 8.9E+07 5.1E+07 7.0E+07 182 P62918 60S ribosomal protein L8 RPL8 4 21.0 28.0 257 18 5.6E+07 5.3E+07 4.4E+07 3.7E+07 4.6E+07 4.6E+07 183 P29341 Polyadenylate-binding protein 1 PABPC1 15 27.7 70.7 636 95 5.6E+07 6.0E+07 3.2E+07 3.4E+07 4.4E+07 5.0E+07 184 P03930 ATP synthase protein 8 MTATP8 3 46.3 7.8 67 19 5.5E+07 7.9E+07 6.1E+07 7.4E+07 9.8E+07 1.1E+08 185 Q99JI6 Ras-related protein Rap-1b RAP1B 5 33.2 20.8 184 80 5.5E+07 5.0E+07 5.6E+07 4.8E+07 6.3E+07 6.7E+07 186 P09055 Integrin beta-1 ITGB1 14 23.4 88.2 798 112 5.4E+07 5.1E+07 5.4E+07 3.5E+07 4.3E+07 4.4E+07 187 Q61990 Poly(rC)-binding protein 2 PCBP2 6 23.8 38.2 362 55 5.4E+07 3.8E+07 4.4E+07 4.4E+07 1.5E+07 2.5E+07 188 Q9CZX8 40S ribosomal protein S19 RPS19 8 41.4 16.1 145 34 5.4E+07 6.0E+07 2.8E+07 2.8E+07 7.2E+07 5.4E+07 189 O54724 Polymerase I and transcript release factor PTRF 10 33.9 44.0 392 234 5.4E+07 7.7E+07 2.9E+07 8.3E+06 7.9E+06 4.6E+06 190 Q61335 B-cell receptor-associated protein 31 BCAP31 4 14.7 28.0 245 66 5.3E+07 4.1E+07 4.2E+07 2.7E+07 2.9E+07 2.5E+07 Phosphoenolpyruvate carboxykinase [GTP], 191 Q8BH04 PCK2 12 22.5 70.5 640 92 5.2E+07 4.4E+07 4.9E+07 2.0E+07 1.7E+07 2.4E+07 mitochondrial Transmembrane emp24 domain-containing 192 Q9BVK6 TMED9 4 12.8 27.3 235 48 5.1E+07 4.5E+07 5.2E+07 2.6E+07 2.7E+07 3.0E+07 protein 9 193 P70372 ELAV-like protein 1 ELAVL1 5 17.8 36.2 326 32 5.1E+07 4.5E+07 3.5E+07 4.0E+07 4.5E+07 4.0E+07 194 Q9D379 Epoxide hydrolase 1 EPHX1 14 38.7 52.6 455 67 5.1E+07 6.0E+07 4.9E+07 5.3E+07 8.2E+07 7.3E+07 195 Q62351 Transferrin receptor protein 1 TFRC 20 27.8 85.7 763 146 5.1E+07 3.7E+07 3.0E+07 6.9E+07 7.6E+07 5.6E+07 196 Q99K85 Phosphoserine aminotransferase PSAT1 9 29.2 40.5 370 70 5.1E+07 5.0E+07 5.9E+07 2.7E+07 1.5E+07 2.4E+07 197 Q791V5 Mitochondrial carrier homolog 2 MTCH2 7 41.3 33.5 303 84 5.1E+07 3.8E+07 4.8E+07 9.9E+07 1.0E+08 9.3E+07 198 P62962 Profilin-1 PFN1 9 84.3 15.0 140 73 5.1E+07 7.8E+07 9.0E+07 1.2E+08 6.6E+07 7.6E+07 Lysosome-associated membrane glycoprotein 199 P11438 LAMP1 6 18.0 43.9 406 173 5.0E+07 5.8E+07 5.9E+07 1.1E+08 1.7E+08 1.5E+08 1 200 P48036 Annexin A5 ANXA5 8 30.7 35.8 319 76 5.0E+07 4.5E+07 5.8E+07 4.3E+07 3.5E+07 3.3E+07 201 Q8R081 Heterogeneous nuclear ribonucleoprotein L HNRNPL 12 38.1 64.0 586 115 5.0E+07 6.3E+07 8.8E+07 3.4E+07 2.8E+07 2.3E+07 Lysosome-associated membrane glycoprotein 202 P17047 LAMP2 5 10.8 45.7 415 26 5.0E+07 4.1E+07 3.8E+07 2.5E+07 4.3E+07 2.6E+07 2 203 Q99020 Heterogeneous nuclear ribonucleoprotein A/B HNRNPAB 7 23.5 30.8 285 95 5.0E+07 6.5E+07 5.6E+07 5.0E+07 4.2E+07 2.8E+07 204 P37040 NADPH--cytochrome P450 reductase POR 18 41.3 77.0 678 270 5.0E+07 5.5E+07 5.8E+07 6.2E+07 7.5E+07 7.9E+07 205 P07901 Heat shock protein HSP 90-alpha HSP90AA1 19 41.9 84.8 733 271 4.9E+07 6.0E+07 6.9E+07 1.3E+08 1.3E+08 1.5E+08 206 Q9D8N0 Elongation factor 1-gamma EEF1G 12 36.8 50.1 437 96 4.8E+07 4.0E+07 2.1E+07 5.0E+07 5.3E+07 4.7E+07 207 P12235 ADP/ATP translocase 1 SLC25A4 2 46.3 33.1 298 3 4.7E+07 4.6E+07 6.1E+07 5.6E+07 9.0E+07 0.0E+00 208 P60710 Actin, cytoplasmic 1 ACTB 1 93.1 41.7 375 62 4.7E+07 3.9E+07 4.6E+07 2.8E+07 2.4E+07 2.8E+07 209 P26443 Glutamate dehydrogenase 1, mitochondrial GLUD1 12 25.6 61.3 558 32 4.7E+07 3.1E+07 4.9E+07 4.3E+07 3.7E+07 3.7E+07 210 Q6ZWV7 60S ribosomal protein L35 RPL35 3 26.0 14.6 123 31 4.6E+07 4.2E+07 3.5E+07 3.1E+07 3.9E+07 2.9E+07 211 Q9CPR4 60S ribosomal protein L17 RPL17 4 27.2 21.4 184 64 4.6E+07 5.5E+07 4.7E+07 5.9E+07 6.5E+07 5.9E+07 212 Q9Z2X1 Heterogeneous nuclear ribonucleoprotein F HNRNPF 7 32.5 45.7 415 192 4.6E+07 4.9E+07 3.0E+07 3.0E+07 2.9E+07 3.1E+07 213 P0DP28 4 30.9 16.8 149 59 4.6E+07 4.4E+07 2.4E+07 3.9E+07 2.7E+07 7.5E+07 214 P58771 Tropomyosin alpha-1 chain TPM1 5 12.3 32.7 284 31 4.5E+07 4.5E+07 5.2E+07 0.0E+00 0.0E+00 0.0E+00 215 P62889 60S ribosomal protein L30 RPL30 3 31.3 12.8 115 39 4.5E+07 5.9E+07 5.0E+07 4.9E+07 6.4E+07 6.5E+07 Neuroblast differentiation-associated protein 216 Q09666 AHNAK 6 5.3 629.1 5890 21 4.5E+07 7.6E+07 4.2E+07 4.3E+07 5.1E+07 5.1E+07 AHNAK Mitochondrial 10-formyltetrahydrofolate 217 Q8K009 ALDH1L2 22 31.3 101.6 923 235 4.5E+07 4.6E+07 5.9E+07 2.4E+07 1.4E+07 1.1E+07 dehydrogenase Dolichyl-diphosphooligosaccharide--protein 218 Q9DBG6 RPN2 18 42.8 69.1 631 176 4.5E+07 4.5E+07 5.0E+07 3.1E+07 3.9E+07 3.8E+07 glycosyltransferase subunit 2 219 P17751 Triosephosphate isomerase TPI1 10 48.2 32.2 299 40 4.5E+07 4.3E+07 4.1E+07 7.1E+07 7.0E+07 8.1E+07 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

220 Q9D0M3 Cytochrome c1, heme protein, mitochondrial CYC1 5 23.1 35.3 325 14 4.5E+07 4.0E+07 4.7E+07 4.2E+07 4.2E+07 5.3E+07 221 P84090 Enhancer of rudimentary homolog ERH 1 10.6 12.3 104 27 4.4E+07 3.6E+07 4.2E+07 6.4E+07 5.2E+07 7.7E+07 222 Q921F2 TAR DNA-binding protein 43 TARDBP 9 37.9 44.5 414 81 4.4E+07 4.6E+07 3.9E+07 2.2E+07 2.1E+07 2.0E+07 Cytochrome c oxidase subunit 6A1, 223 P43024 COX6A1 3 35.1 12.4 111 9 4.4E+07 6.1E+07 5.6E+07 2.6E+07 1.9E+07 3.8E+07 mitochondrial NADH dehydrogenase [ubiquinone] 1 alpha 224 Q9CQZ5 NDUFA6 2 12.2 15.3 131 2 4.4E+07 8.6E+06 8.2E+06 7.9E+06 0.0E+00 0.0E+00 subcomplex subunit 6 225 Q01768 Nucleoside diphosphate kinase B NME2 10 73.7 17.4 152 75 4.3E+07 4.5E+07 5.6E+07 2.1E+08 1.4E+08 1.6E+08 226 P60953 Cell division control protein 42 homolog CDC42 6 45.5 21.3 191 49 4.3E+07 3.8E+07 3.9E+07 4.0E+07 3.7E+07 4.5E+07 227 P08207 Protein S100-A10 S100A10 3 27.8 11.2 97 18 4.2E+07 4.3E+07 3.3E+07 2.4E+07 4.1E+07 4.4E+07 Supplementary file 4A : (continued) 228 Q01320 DNA topoisomerase 2-alpha TOP2A 24 18.8 172.8 1528 118 4.2E+07 4.7E+07 4.6E+07 3.7E+07 3.4E+07 2.9E+07 229 Q60668 Heterogeneous nuclear ribonucleoprotein D0 HNRNPD 5 14.9 38.4 355 35 4.2E+07 4.1E+07 4.1E+07 3.1E+07 2.2E+07 2.5E+07 230 Q8BHN3 Neutral alpha-glucosidase AB GANAB 35 46.3 106.9 944 173 4.1E+07 4.4E+07 1.1E+08 1.2E+08 8.1E+07 9.2E+07 231 P99027 60S acidic ribosomal protein P2 RPLP2 4 47.8 11.7 115 93 4.1E+07 5.2E+07 2.3E+07 2.2E+07 8.9E+07 6.6E+07 232 Q9CPQ1 Cytochrome c oxidase subunit 6C COX6C 4 50.0 8.5 76 7 4.1E+07 5.1E+07 5.2E+07 5.7E+07 6.5E+07 1.5E+08 233 P36542 ATP synthase subunit gamma, mitochondrial ATP5C1 1 11.1 33.0 298 3 4.1E+07 3.3E+07 3.6E+07 4.1E+07 7.3E+07 4.9E+07 234 Q91V41 Ras-related protein Rab-14 RAB14 6 44.7 23.9 215 73 4.0E+07 3.7E+07 3.7E+07 2.5E+07 4.0E+07 3.8E+07 235 P46782 40S ribosomal protein S5 RPS5 4 27.9 22.9 204 97 4.0E+07 4.3E+07 4.1E+07 3.1E+07 4.3E+07 3.7E+07 Membrane-associated progesterone receptor 236 Q80UU9 PGRMC2 4 26.7 23.3 217 19 3.9E+07 4.0E+07 4.5E+07 3.9E+07 3.4E+07 3.8E+07 component 2 237 P14115 60S ribosomal protein L27a RPL27A 7 37.2 16.6 148 45 3.9E+07 4.6E+07 3.7E+07 5.1E+07 5.0E+07 5.1E+07 Calcium-binding mitochondrial carrier protein 238 Q8BH59 SLC25A12 18 36.8 74.6 677 139 3.9E+07 3.4E+07 3.5E+07 8.4E+07 6.8E+07 7.6E+07 Aralar1 239 P13020 Gelsolin GSN 13 27.6 85.9 780 125 3.9E+07 3.0E+07 3.8E+07 2.4E+07 2.5E+07 4.0E+07 240 P62852 40S ribosomal protein S25 RPS25 4 24.0 13.7 125 22 3.8E+07 4.4E+07 3.4E+07 3.4E+07 5.2E+07 3.8E+07 241 Q9DBJ1 Phosphoglycerate mutase 1 PGAM1 7 42.1 28.8 254 52 3.8E+07 6.2E+07 6.5E+07 1.2E+08 7.5E+07 1.1E+08 242 Q8K310 Matrin-3 MATR3 12 22.0 94.6 846 113 3.7E+07 4.2E+07 1.8E+07 3.5E+07 3.0E+07 2.8E+07 243 P10639 Thioredoxin TXN 5 54.3 11.7 105 28 3.7E+07 4.5E+07 4.2E+07 6.9E+07 3.3E+07 5.8E+07 244 P61358 60S ribosomal protein L27 RPL27 3 27.9 15.8 136 7 3.7E+07 5.3E+07 5.7E+07 4.9E+07 4.8E+07 4.8E+07 245 P84099 60S ribosomal protein L19 RPL19 2 13.3 23.5 196 79 3.7E+07 4.6E+07 3.0E+07 2.5E+07 2.9E+07 2.3E+07 246 Q9R0X4 Acyl-coenzyme A thioesterase 9, mitochondrial ACOT9 15 35.8 50.6 439 44 3.7E+07 3.4E+07 5.4E+07 7.5E+07 6.8E+07 5.9E+07

247 P47758 Signal recognition particle receptor subunit beta SRPRB 6 33.8 29.6 269 40 3.6E+07 3.5E+07 3.1E+07 3.0E+07 3.7E+07 4.1E+07 248 Q9NP72 Ras-related protein Rab-18 RAB18 9 57.8 23.0 206 128 3.6E+07 3.1E+07 3.4E+07 4.2E+07 4.9E+07 4.5E+07 Membrane-associated progesterone receptor 249 O55022 PGRMC1 5 42.1 21.7 195 49 3.6E+07 3.7E+07 4.2E+07 4.5E+07 4.6E+07 6.8E+07 component 1 250 P62267 40S ribosomal protein S23 RPS23 4 35.0 15.8 143 35 3.6E+07 3.6E+07 3.1E+07 2.8E+07 3.4E+07 3.0E+07 251 Q9D0E1 Heterogeneous nuclear ribonucleoprotein M HNRNPM 8 15.1 77.6 729 44 3.6E+07 3.9E+07 2.1E+07 1.6E+07 2.1E+07 2.1E+07 Synaptic vesicle membrane protein VAT-1 252 Q62465 VAT1 12 36.9 43.1 406 176 3.5E+07 5.6E+07 6.7E+07 4.4E+07 5.4E+07 5.4E+07 homolog Isocitrate dehydrogenase [NAD] subunit alpha, 253 Q9D6R2 IDH3A 8 26.8 39.6 366 52 3.5E+07 2.7E+07 3.8E+07 9.8E+07 1.1E+08 1.4E+08 mitochondrial 254 Q8R1I1 Cytochrome b-c1 complex subunit 9 UQCR10 3 50.0 7.4 64 31 3.5E+07 4.9E+07 4.0E+07 5.4E+07 5.1E+07 7.0E+07 255 Q60597 2-oxoglutarate dehydrogenase, mitochondrial OGDH 21 27.0 116.5 1023 77 3.5E+07 3.7E+07 2.3E+07 5.7E+07 4.8E+07 5.1E+07

256 Q01853 Transitional endoplasmic reticulum ATPase VCP 13 23.6 89.3 806 78 3.4E+07 4.0E+07 3.1E+07 3.5E+07 3.0E+07 2.8E+07 Pyruvate dehydrogenase E1 component subunit 257 Q9D051 PDHB 8 30.1 38.9 359 62 3.4E+07 3.2E+07 3.0E+07 5.3E+07 4.9E+07 4.3E+07 beta, mitochondrial Vacuolar ATPase assembly integral membrane 258 Q78T54 VMA21 2 21.8 11.4 101 6 3.4E+07 3.4E+07 3.5E+07 1.6E+07 1.9E+07 2.0E+07 protein Vma21 259 Q6ZWU9 40S ribosomal protein S27 RPS27 3 38.1 9.5 84 16 3.3E+07 3.7E+07 5.1E+07 4.6E+07 3.7E+07 5.0E+07 Guanine nucleotide-binding protein 260 P62880 GNB2 6 44.4 37.3 340 62 3.3E+07 2.7E+07 3.5E+07 2.8E+07 2.5E+07 3.5E+07 G(I)/G(S)/G(T) subunit beta-2 261 P62317 Small nuclear ribonucleoprotein Sm D2 SNRPD2 5 38.1 13.5 118 52 3.3E+07 2.8E+07 3.6E+07 3.8E+07 3.4E+07 3.7E+07 262 Q91VC3 Eukaryotic initiation factor 4A-III EIF4A3 11 31.9 46.8 411 50 3.3E+07 3.6E+07 3.7E+07 2.3E+07 2.0E+07 2.5E+07 263 Q6ZWV3 60S ribosomal protein L10 RPL10 4 18.2 24.6 214 8 3.3E+07 3.3E+07 3.3E+07 4.8E+07 4.1E+07 3.7E+07 Staphylococcal nuclease domain-containing 264 Q78PY7 SND1 18 29.1 102.1 910 120 3.3E+07 3.8E+07 2.5E+07 2.6E+07 2.4E+07 2.2E+07 protein 1 265 P62320 Small nuclear ribonucleoprotein Sm D3 SNRPD3 3 20.6 13.9 126 7 3.3E+07 3.3E+07 3.7E+07 4.1E+07 2.8E+07 2.1E+07 266 P84078 ADP-ribosylation factor 1 ARF1 7 50.3 20.7 181 85 3.3E+07 2.4E+07 3.4E+07 2.7E+07 2.0E+07 3.2E+07 267 Q8QZT1 Acetyl-CoA acetyltransferase, mitochondrial ACAT1 9 26.2 44.8 424 119 3.2E+07 3.8E+07 4.4E+07 7.4E+07 5.7E+07 6.6E+07 268 P35282 Ras-related protein Rab-21 RAB21 7 39.2 24.1 222 54 3.2E+07 2.4E+07 2.5E+07 4.9E+07 4.9E+07 5.7E+07 269 Q9CQX2 Cytochrome b5 type B CYB5B 3 41.8 16.3 146 22 3.2E+07 3.3E+07 3.2E+07 4.5E+07 2.6E+07 3.4E+07 270 P09411 Phosphoglycerate kinase 1 PGK1 9 28.3 44.6 417 82 3.2E+07 3.4E+07 2.2E+07 4.4E+07 4.2E+07 5.4E+07 271 P29391 Ferritin light chain 1 FTL1 4 29.5 20.8 183 30 3.1E+07 2.8E+07 2.7E+07 2.6E+07 2.0E+07 2.0E+07 Thioredoxin-dependent peroxide reductase, 272 P20108 PRDX3 5 21.0 28.1 257 19 3.1E+07 3.2E+07 3.4E+07 5.0E+07 2.9E+07 4.4E+07 mitochondrial 273 P56395 Cytochrome b5 CYB5A 5 47.8 15.2 134 14 3.1E+07 2.7E+07 3.0E+07 3.4E+07 4.7E+07 5.7E+07 274 Q9DBS1 Transmembrane protein 43 TMEM43 6 22.2 44.8 400 24 3.1E+07 1.9E+07 2.4E+07 8.2E+06 1.6E+07 1.4E+07 275 P10107 Annexin A1 ANXA1 9 36.4 38.7 346 210 3.1E+07 3.7E+07 3.3E+07 5.1E+07 3.8E+07 4.5E+07 276 Q9CY50 Translocon-associated protein subunit alpha SSR1 3 11.9 32.1 286 91 3.1E+07 3.9E+07 4.8E+07 2.7E+07 2.6E+07 2.2E+07 Sarcoplasmic/endoplasmic reticulum calcium 277 P16615 ATP2A2 9 11.5 114.8 1042 36 3.1E+07 3.0E+07 3.2E+07 3.5E+07 3.8E+07 3.7E+07 ATPase 2 278 P62264 40S ribosomal protein S14 RPS14 4 49.7 16.3 151 14 3.0E+07 2.9E+07 2.1E+07 3.1E+07 3.5E+07 3.0E+07 Cytochrome b-c1 complex subunit 6, 279 P99028 UQCRH 3 44.9 10.4 89 13 3.0E+07 2.6E+07 3.3E+07 3.7E+07 2.4E+07 3.3E+07 mitochondrial 280 Q91VM5 RNA binding motif protein, X-linked-like-1 RBMXL1 6 16.5 42.2 388 68 3.0E+07 2.4E+07 1.6E+07 7.4E+06 1.3E+07 1.1E+07 Succinate dehydrogenase [ubiquinone] iron- 281 Q9CQA3 SDHB 5 20.6 31.8 282 20 2.9E+07 3.1E+07 3.2E+07 2.3E+07 2.1E+07 2.5E+07 sulfur subunit, mitochondrial 282 P11276 Fibronectin FN1 18 10.9 272.5 2477 126 2.9E+07 3.0E+07 2.9E+07 1.1E+07 0.0E+00 0.0E+00 283 P10404 MLV-related proviral Env polyprotein FV4 2 3.3 69.6 641 25 2.9E+07 2.8E+07 4.3E+07 2.1E+07 2.1E+07 8.5E+06 284 O09167 60S ribosomal protein L21 RPL21 1 9.4 18.6 160 29 2.9E+07 4.4E+07 7.4E+06 1.4E+07 9.7E+06 7.0E+06 285 O89086 RNA-binding protein 3 RBM3 2 32.7 16.6 153 18 2.9E+07 3.3E+07 2.2E+07 9.7E+06 9.0E+06 1.5E+07 Procollagen-lysine,2-oxoglutarate 5- 286 Q9R0E1 PLOD3 14 27.8 84.9 741 103 2.9E+07 2.8E+07 3.6E+07 1.7E+07 2.4E+07 2.1E+07 dioxygenase 3 Trifunctional enzyme subunit alpha, 287 Q8BMS1 HADHA 17 30.4 82.7 763 180 2.8E+07 2.4E+07 2.6E+07 8.3E+07 4.6E+07 6.8E+07 mitochondrial 288 P68372 Tubulin beta-4B chain TUBB4B 6 60.4 49.8 445 81 2.8E+07 2.6E+07 2.4E+07 2.9E+07 3.7E+07 2.5E+07 Pyruvate dehydrogenase E1 component subunit 289 P35486 PDHA1 9 32.3 43.2 390 46 2.8E+07 2.4E+07 3.1E+07 4.3E+07 4.5E+07 4.8E+07 alpha, somatic form, mitochondrial 290 O75396 Vesicle-trafficking protein SEC22b SEC22B 5 30.2 24.6 215 79 2.8E+07 1.8E+07 2.6E+07 6.6E+06 1.4E+07 2.2E+07 291 Q01149 Collagen alpha-2(I) chain COL1A2 16 20.3 129.6 1372 92 2.8E+07 4.0E+07 4.7E+07 0.0E+00 3.1E+06 4.6E+06 292 Q9D3D9 ATP synthase subunit delta, mitochondrial ATP5D 3 28.6 17.6 168 13 2.8E+07 1.0E+07 1.6E+07 4.8E+07 4.7E+07 4.7E+07 293 P50543 Protein S100-A11 S100A11 3 34.7 11.1 98 84 2.7E+07 2.1E+07 1.6E+07 2.2E+07 2.6E+07 2.9E+07 Mitochondrial import receptor subunit TOM22 294 Q9CPQ3 TOMM22 3 33.8 15.5 142 28 2.7E+07 1.9E+07 2.3E+07 4.1E+07 3.5E+07 4.1E+07 homolog 295 Q8CGK3 Lon protease homolog, mitochondrial LONP1 16 24.2 105.8 949 120 2.7E+07 2.2E+07 2.9E+07 2.4E+07 2.2E+07 2.6E+07 296 P62259 14-3-3 protein epsilon YWHAE 7 40.0 29.2 255 111 2.7E+07 3.5E+07 4.3E+07 6.6E+07 8.8E+07 7.3E+07 297 Q60973 Histone-binding protein RBBP7 RBBP7 7 23.8 47.8 425 32 2.7E+07 2.3E+07 2.0E+07 1.6E+07 1.7E+07 1.5E+07 298 P05064 Fructose-bisphosphate aldolase A ALDOA 18 74.2 39.4 364 168 2.6E+07 2.8E+07 2.9E+07 8.8E+07 9.4E+07 1.4E+08 Protein transport protein Sec61 subunit alpha 299 P61620 SEC61A1 6 18.9 52.3 476 141 2.6E+07 2.1E+07 2.1E+07 5.8E+06 1.3E+07 1.6E+07 isoform 1 300 O70251 Elongation factor 1-beta EEF1B 3 26.7 24.7 225 76 2.6E+07 2.5E+07 1.7E+07 3.3E+07 3.2E+07 3.2E+07 301 Q9QUI0 Transforming protein RhoA RHOA 5 38.9 21.8 193 114 2.6E+07 3.0E+07 3.0E+07 2.7E+07 3.3E+07 3.5E+07 Cytochrome b-c1 complex subunit 1, 302 Q9CZ13 UQCRC1 11 23.8 52.9 480 69 2.5E+07 2.8E+07 3.8E+07 2.8E+07 2.7E+07 2.7E+07 mitochondrial 303 Q9ES97 Reticulon-3 RTN3 3 3.2 103.9 964 22 2.5E+07 1.6E+07 2.2E+07 4.0E+07 6.1E+07 6.3E+07 304 P41731 CD63 antigen CD63 3 11.8 25.8 238 8 2.5E+07 3.0E+07 1.5E+07 1.4E+07 2.7E+07 2.3E+07 KH domain-containing, RNA-binding, signal 305 Q60749 KHDRBS1 5 12.4 48.4 443 47 2.5E+07 2.7E+07 2.4E+07 1.9E+07 2.4E+07 2.6E+07 transduction-associated protein 1 306 Q9CRB9 MICOS complex subunit Mic19 CHCHD3 4 20.7 26.3 227 12 2.5E+07 2.4E+07 2.2E+07 1.9E+07 2.2E+07 2.1E+07 307 P52272 Heterogeneous nuclear ribonucleoprotein M HNRNPM 1 14.4 77.5 730 -2 2.4E+07 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 308 Q99PT1 Rho GDP-dissociation inhibitor 1 ARHGDIA 4 39.2 23.4 204 17 2.4E+07 3.0E+07 2.4E+07 3.1E+07 1.7E+07 1.7E+07 Mitochondrial import inner membrane 309 Q9D880 TIMM50 6 21.5 39.8 353 81 2.4E+07 2.7E+07 3.0E+07 3.8E+07 3.3E+07 3.2E+07 translocase subunit TIM50 310 P56959 RNA-binding protein FUS FUS 3 6.4 52.7 518 5 2.4E+07 1.1E+07 0.0E+00 0.0E+00 9.5E+06 6.9E+06 311 P03975 IgE-binding protein IAP 7 16.5 62.7 557 15 2.4E+07 3.2E+07 2.4E+07 1.1E+07 1.5E+07 1.1E+07 Glycerol-3-phosphate dehydrogenase, 312 Q64521 GPD2 14 26.5 81.0 727 84 2.3E+07 2.9E+07 2.8E+07 4.6E+07 6.0E+07 5.8E+07 mitochondrial 313 P57776 Elongation factor 1-delta EEF1D 4 16.4 31.3 281 89 2.3E+07 3.2E+07 2.5E+07 3.5E+07 4.4E+07 4.2E+07 314 Q9DCW4 Electron transfer flavoprotein subunit beta ETFB 5 23.9 27.6 255 10 2.3E+07 1.7E+07 1.8E+07 2.6E+07 2.4E+07 2.7E+07 315 P16546 Spectrin alpha chain, non-erythrocytic 1 SPTAN1 16 8.5 284.6 2472 62 2.3E+07 1.3E+07 1.7E+07 8.0E+06 3.4E+06 5.3E+06 316 P62315 Small nuclear ribonucleoprotein Sm D1 SNRPD1 3 37.0 13.3 119 31 2.3E+07 1.8E+07 3.0E+07 2.6E+07 2.4E+07 2.9E+07 Sodium/potassium-transporting ATPase subunit 317 Q8VDN2 ATP1A1 10 12.1 113.0 1023 44 2.3E+07 2.2E+07 2.4E+07 2.0E+07 3.2E+07 2.2E+07 alpha-1 318 Q9CWP6 Motile sperm domain-containing protein 2 MOSPD2 8 20.3 59.9 518 31 2.3E+07 2.1E+07 1.3E+07 1.3E+07 1.3E+07 1.0E+07 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

319 Q64012 RNA-binding protein Raly RALY 4 12.8 33.2 312 16 2.3E+07 2.3E+07 2.0E+07 1.6E+07 1.7E+07 1.8E+07 NADH dehydrogenase [ubiquinone] 1 beta 320 Q9DCS9 NDUFB10 4 31.8 21.0 176 39 2.3E+07 1.8E+07 1.7E+07 2.2E+07 2.4E+07 2.3E+07 subcomplex subunit 10 Dihydrolipoyllysine-residue acetyltransferase 321 Q8BMF4 component of pyruvate dehydrogenase DLAT 10 20.2 67.9 642 34 2.3E+07 1.4E+07 1.7E+07 3.9E+07 3.9E+07 4.6E+07 complex, mitochondrial 322 Q7TPV4 Myb-binding protein 1A MYBBP1A 15 15.4 152.0 1344 83 2.3E+07 3.1E+07 2.4E+07 2.6E+07 2.8E+07 2.7E+07 323 Q9DB73 NADH-cytochrome b5 reductase 1 CYB5R1 4 20.0 34.1 305 45 2.2E+07 2.2E+07 1.9E+07 2.0E+07 1.4E+07 1.5E+07 324 Q9CQ65 S-methyl-5-thioadenosine phosphorylase MTAP 4 21.9 31.1 283 23 2.2E+07 2.5E+07 2.9E+07 2.9E+07 2.2E+07 3.0E+07 325 P31947 14-3-3 protein sigma SFN 1 13.3 27.8 248 -2 2.2E+07 0.0E+00 7.1E+06 8.2E+06 0.0E+00 0.0E+00 326 Q7TNS2 MICOS complex subunit Mic10 MINOS1 1 9.2 8.6 76 2 2.2E+07 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 327 Q7TMK9 Heterogeneous nuclear ribonucleoprotein Q SYNCRIP 5 11.4 69.6 623 82 2.2E+07 1.2E+07 1.2E+07 1.1E+07 1.4E+07 1.5E+07 328 P63242 Eukaryotic translation initiation factor 5A-1 EIF5A 4 27.9 16.8 154 59 2.2E+07 2.0E+07 2.9E+07 2.4E+07 1.7E+07 2.4E+07 329 Q8R2Y8 Peptidyl-tRNA hydrolase 2, mitochondrial PTRH2 4 37.6 19.5 181 117 2.2E+07 2.2E+07 2.8E+07 4.3E+07 3.5E+07 4.3E+07 330 Q62167 ATP-dependent RNA helicase DDX3X DDX3X 7 15.1 73.1 662 91 2.2E+07 2.1E+07 1.2E+07 1.1E+07 1.0E+07 8.7E+06 Supplementary file 4A : (continued) 331 Q58FF8 Putative heat shock protein HSP 90-beta 2 HSP90AB2P 2 20.2 44.3 381 17 2.2E+07 1.8E+07 1.5E+07 1.7E+07 1.9E+07 2.4E+07 332 P31943 Heterogeneous nuclear ribonucleoprotein H HNRNPH1 3 16.3 49.2 449 132 2.1E+07 2.2E+07 1.6E+07 6.8E+06 1.2E+07 8.3E+06 333 P27046 Alpha-mannosidase 2 MAN2A1 10 11.2 131.6 1150 23 2.1E+07 1.8E+07 1.6E+07 9.8E+06 5.4E+06 8.7E+06 334 Q9D6Z1 Nucleolar protein 56 NOP56 11 23.6 64.5 580 30 2.1E+07 2.6E+07 2.0E+07 2.1E+07 2.2E+07 2.4E+07 335 P26041 Moesin MSN 7 13.9 67.8 577 73 2.1E+07 2.5E+07 1.9E+07 1.4E+07 2.3E+07 2.6E+07 336 P62305 Small nuclear ribonucleoprotein E SNRPE 2 39.1 10.8 92 11 2.0E+07 1.3E+07 1.3E+07 0.0E+00 9.3E+06 1.0E+07 337 Q9JIK5 Nucleolar RNA helicase 2 DDX21 9 13.6 93.6 851 21 2.0E+07 2.6E+07 1.4E+07 1.8E+07 1.8E+07 1.5E+07 338 O08749 Dihydrolipoyl dehydrogenase, mitochondrial DLD 7 18.9 54.3 509 40 2.0E+07 1.3E+07 1.5E+07 2.8E+07 3.1E+07 3.2E+07 339 P62274 40S ribosomal protein S29 RPS29 1 19.6 6.7 56 7 2.0E+07 2.6E+07 1.7E+07 2.3E+07 2.3E+07 2.9E+07 340 Q9CR67 Transmembrane protein 33 TMEM33 3 12.6 28.0 247 32 1.9E+07 1.8E+07 2.0E+07 2.4E+07 2.3E+07 2.2E+07 341 Q9Z0X1 Apoptosis-inducing factor 1, mitochondrial AIFM1 11 27.0 66.8 612 70 1.9E+07 2.2E+07 3.4E+07 1.4E+07 1.4E+07 2.6E+07 342 P62849 40S ribosomal protein S24 RPS24 2 20.3 15.4 133 19 1.9E+07 4.2E+07 1.9E+07 2.2E+07 1.3E+07 1.3E+07 Mitochondrial 2-oxoglutarate/malate carrier 343 Q9CR62 SLC25A11 6 26.8 34.2 314 22 1.9E+07 2.2E+07 1.9E+07 3.0E+07 4.0E+07 3.6E+07 protein 344 P62307 Small nuclear ribonucleoprotein F SNRPF 4 33.7 9.7 86 6 1.9E+07 2.1E+07 2.1E+07 2.1E+07 1.8E+07 0.0E+00 Mitochondrial import receptor subunit TOM40 345 Q9QYA2 TOMM40 7 21.9 37.9 361 28 1.9E+07 1.5E+07 1.4E+07 1.4E+07 1.7E+07 2.0E+07 homolog 346 P18077 60S ribosomal protein L35a RPL35A 3 25.5 12.5 110 7 1.9E+07 2.0E+07 1.9E+07 3.0E+07 1.9E+07 1.8E+07 Calcium-binding mitochondrial carrier protein 347 Q8BMD8 SLC25A24 4 9.9 52.9 475 38 1.9E+07 9.4E+06 1.1E+07 1.3E+07 1.7E+07 1.9E+07 SCaMC-1 348 Q9D855 Cytochrome b-c1 complex subunit 7 UQCRB 2 20.7 13.5 111 10 1.9E+07 1.4E+07 1.6E+07 1.3E+07 1.7E+07 1.9E+07 Serine/threonine-protein phosphatase PP1- 349 P63087 PPP1CC 8 31.9 37.0 323 113 1.9E+07 2.4E+07 1.9E+07 2.2E+07 2.8E+07 2.4E+07 gamma catalytic subunit 350 O88441 Metaxin-2 MTX2 4 18.6 29.8 263 12 1.9E+07 2.5E+07 1.4E+07 2.4E+07 2.0E+07 7.9E+06 Pre-mRNA-splicing factor ATP-dependent RNA 351 O43143 DHX15 12 19.1 90.9 795 44 1.9E+07 2.1E+07 2.2E+07 1.7E+07 1.9E+07 2.0E+07 helicase DHX15 352 P84104 Serine/arginine-rich splicing factor 3 SRSF3 4 25.6 19.3 164 14 1.8E+07 2.4E+07 1.0E+07 1.5E+07 1.9E+07 1.7E+07 353 Q9CQL1 Protein mago nashi homolog 2 MAGOHB 5 45.2 17.1 146 20 1.8E+07 1.5E+07 2.0E+07 2.3E+07 1.8E+07 2.4E+07 354 Q9R1Q7 Proteolipid protein 2 PLP2 2 18.4 16.6 152 29 1.8E+07 9.6E+06 1.8E+07 8.8E+06 1.6E+07 1.9E+07 355 Q9WTP6 Adenylate kinase 2, mitochondrial AK2 5 30.1 26.5 239 17 1.8E+07 1.6E+07 1.7E+07 1.4E+07 1.3E+07 1.3E+07 356 P61982 14-3-3 protein gamma YWHAG 2 19.4 28.3 247 66 1.7E+07 1.4E+07 0.0E+00 0.0E+00 0.0E+00 0.0E+00 357 P60843 Eukaryotic initiation factor 4A-I EIF4A1 7 30.8 46.2 406 71 1.7E+07 1.9E+07 1.9E+07 2.1E+07 1.3E+07 1.6E+07 358 Q61207 Prosaposin PSAP 4 9.0 61.4 557 9 1.7E+07 1.3E+07 2.5E+07 1.3E+07 1.1E+07 1.5E+07 359 Q61753 D-3-phosphoglycerate dehydrogenase PHGDH 7 16.1 56.6 533 75 1.7E+07 2.0E+07 2.2E+07 1.6E+07 1.2E+07 1.2E+07 360 Q9D0T1 NHP2-like protein 1 NHP2L1 3 27.3 14.2 128 33 1.7E+07 1.8E+07 1.4E+07 1.9E+07 1.5E+07 1.6E+07 361 P62960 Nuclease-sensitive element-binding protein 1 YBX1 2 11.2 35.7 322 57 1.7E+07 1.5E+07 5.8E+06 4.4E+06 3.5E+06 4.2E+06 362 Q9QZQ8 Core histone macro-H2A.1 H2AFY 6 23.4 39.7 372 43 1.7E+07 2.1E+07 2.1E+07 1.2E+07 1.4E+07 1.0E+07 363 Q62261 Spectrin beta chain, non-erythrocytic 1 SPTBN1 18 10.3 274.2 2363 88 1.6E+07 1.3E+07 2.3E+07 8.9E+06 7.4E+06 4.3E+06 NADH-ubiquinone oxidoreductase 75 kDa 364 Q91VD9 NDUFS1 7 13.8 79.8 727 63 1.6E+07 1.4E+07 1.8E+07 1.9E+07 1.6E+07 1.8E+07 subunit, mitochondrial Mitochondrial import receptor subunit TOM20 365 Q9DCC8 TOMM20 2 18.6 16.3 145 7 1.6E+07 0.0E+00 1.2E+07 1.1E+07 1.2E+07 1.7E+07 homolog 366 Q14974 Importin subunit beta-1 KPNB1 11 17.1 97.2 876 156 1.6E+07 1.4E+07 1.1E+07 1.7E+07 2.5E+07 2.3E+07 367 P62858 40S ribosomal protein S28 RPS28 2 30.4 7.8 69 24 1.6E+07 2.1E+07 1.8E+07 2.1E+07 1.9E+07 2.0E+07 368 Q9D0M5 Dynein light chain 2, cytoplasmic DYNLL2 2 24.7 10.4 89 13 1.5E+07 1.8E+07 2.0E+07 2.4E+07 2.2E+07 1.9E+07 369 Q9CQD1 Ras-related protein Rab-5A RAB5A 4 37.7 23.6 215 27 1.5E+07 1.1E+07 1.1E+07 9.5E+06 1.0E+07 1.2E+07 370 P46935 E3 ubiquitin-protein ligase NEDD4 NEDD4 9 12.2 102.7 887 33 1.5E+07 1.9E+07 1.7E+07 1.2E+07 8.5E+06 9.4E+06 NADH dehydrogenase [ubiquinone] iron-sulfur 371 Q9DCT2 NDUFS3 5 24.7 30.1 263 44 1.5E+07 1.1E+07 7.6E+06 1.2E+07 8.2E+06 7.5E+06 protein 3, mitochondrial 372 P09671 Superoxide dismutase [Mn], mitochondrial SOD2 3 16.7 24.6 222 38 1.5E+07 1.4E+07 2.0E+07 2.7E+07 2.7E+07 2.5E+07 373 P14206 40S ribosomal protein SA RPSA 4 24.4 32.8 295 59 1.5E+07 2.1E+07 1.9E+07 2.2E+07 7.7E+06 1.5E+07 374 Q61941 NAD(P) transhydrogenase, mitochondrial NNT 8 8.9 113.8 1086 27 1.5E+07 1.3E+07 9.8E+06 1.5E+07 1.9E+07 2.4E+07 375 Q9Y3U8 60S ribosomal protein L36 RPL36 3 28.6 12.3 105 16 1.5E+07 2.0E+07 1.6E+07 1.8E+07 1.7E+07 1.7E+07 376 P97855 Ras GTPase-activating protein-binding protein 1 G3BP1 5 15.3 51.8 465 48 1.4E+07 2.6E+07 9.6E+06 6.7E+06 4.7E+06 6.3E+06 377 Q6PDM2 Serine/arginine-rich splicing factor 1 SRSF1 9 37.9 27.7 248 20 1.4E+07 2.5E+07 8.5E+06 1.2E+07 2.7E+07 1.3E+07 378 P63001 Ras-related C3 botulinum toxin substrate 1 RAC1 3 22.4 21.5 192 15 1.4E+07 1.1E+07 1.4E+07 1.7E+07 1.1E+07 1.2E+07 379 P28301 Protein-lysine 6-oxidase LOX 3 11.4 46.7 411 5 1.4E+07 1.0E+07 1.0E+07 0.0E+00 0.0E+00 0.0E+00 380 Q922R8 Protein disulfide-isomerase A6 PDIA6 10 34.8 48.1 440 158 1.4E+07 2.0E+07 5.2E+07 6.1E+07 3.8E+07 5.3E+07 381 Q7TPR4 Alpha-actinin-1 ACTN1 7 30.7 103.1 892 58 1.4E+07 1.1E+07 1.3E+07 4.7E+06 5.5E+06 9.8E+06 382 P30681 High mobility group protein B2 HMGB2 7 33.8 24.2 210 18 1.4E+07 2.5E+07 5.8E+07 1.0E+07 1.0E+07 1.3E+07 383 P61421 V-type proton ATPase subunit d 1 ATP6V0D1 3 10.3 40.3 351 20 1.4E+07 1.5E+07 1.7E+07 1.0E+07 1.0E+07 9.3E+06 3-beta-hydroxysteroid-Delta(8),Delta(7)- 384 P70245 EBP 3 15.2 26.2 230 5 1.4E+07 0.0E+00 1.3E+07 0.0E+00 0.0E+00 0.0E+00 isomerase 385 P19105 Myosin regulatory light chain 12A MYL12A 2 12.3 19.8 171 28 1.4E+07 9.5E+06 8.2E+06 8.9E+06 7.2E+06 3.3E+06 386 Q8TBQ9 Protein kish-A TMEM167A 2 25.0 8.1 72 4 1.4E+07 1.8E+07 1.2E+07 9.3E+06 1.7E+07 1.7E+07 Guanine nucleotide-binding protein 387 Q9DAS9 GNG12 3 47.2 8.0 72 6 1.4E+07 7.8E+06 1.0E+07 8.8E+06 1.2E+07 1.5E+07 G(I)/G(S)/G(O) subunit gamma-12 388 Q9CQR4 Acyl-coenzyme A thioesterase 13 ACOT13 3 25.0 15.2 140 35 1.4E+07 1.1E+07 1.9E+07 5.5E+07 3.2E+07 4.2E+07 389 P27659 60S ribosomal protein L3 RPL3 6 18.4 46.1 403 18 1.4E+07 2.1E+07 1.6E+07 5.0E+06 8.7E+06 6.7E+06 390 Q9DBG3 AP-2 complex subunit beta AP2B1 9 13.7 104.6 937 37 1.4E+07 1.1E+07 1.1E+07 7.2E+06 6.4E+06 1.1E+07 391 Q8BFR5 Elongation factor Tu, mitochondrial TUFM 5 15.7 49.5 452 28 1.3E+07 1.4E+07 1.6E+07 3.0E+07 2.3E+07 2.1E+07 392 Q3U0V1 Far upstream element-binding protein 2 KHSRP 6 9.4 76.8 748 31 1.3E+07 1.3E+07 1.3E+07 1.0E+07 9.7E+06 9.3E+06 393 Q922Q4 Pyrroline-5-carboxylate reductase 2 PYCR2 3 12.5 33.7 320 14 1.3E+07 1.1E+07 1.1E+07 1.1E+07 1.1E+07 1.4E+07 Cleavage and polyadenylation specificity factor 394 Q9CQF3 NUDT21 3 17.2 26.2 227 9 1.3E+07 1.1E+07 6.5E+06 1.1E+07 1.2E+07 1.0E+07 subunit 5 395 Q920B9 FACT complex subunit SPT16 SUPT16H 8 9.8 119.8 1047 29 1.3E+07 1.6E+07 1.7E+07 1.3E+07 1.3E+07 1.0E+07 Electron transfer flavoprotein subunit alpha, 396 Q99LC5 ETFA 6 26.7 35.0 333 45 1.3E+07 2.0E+07 1.8E+07 2.5E+07 2.2E+07 2.0E+07 mitochondrial 397 O00560 Syntenin-1 SDCBP 3 12.1 32.4 298 13 1.3E+07 1.4E+07 1.4E+07 1.2E+07 6.2E+06 9.9E+06 398 P62309 Small nuclear ribonucleoprotein G SNRPG 2 25.0 8.5 76 3 1.3E+07 0.0E+00 2.2E+07 0.0E+00 0.0E+00 0.0E+00 399 Q9DBH5 Vesicular integral-membrane protein VIP36 LMAN2 3 16.2 40.4 358 25 1.3E+07 1.0E+07 1.1E+07 1.2E+07 1.2E+07 1.0E+07 400 P34884 Macrophage migration inhibitory factor MIF 2 26.1 12.5 115 64 1.3E+07 2.1E+07 3.3E+07 4.1E+07 3.1E+07 3.9E+07 401 Q8VBT0 Thioredoxin-related transmembrane protein 1 TMX1 3 13.3 31.4 278 26 1.3E+07 1.1E+07 1.0E+07 1.7E+07 2.0E+07 2.7E+07 402 Q9UQ80 Proliferation-associated protein 2G4 PA2G4 6 18.5 43.8 394 28 1.3E+07 1.5E+07 1.7E+07 9.1E+06 1.0E+07 7.9E+06 403 Q9BV40 Vesicle-associated membrane protein 8 VAMP8 3 24.0 11.4 100 13 1.3E+07 1.4E+07 2.1E+07 2.3E+07 1.7E+07 2.2E+07 404 Q6GQT9 Nodal modulator 1 NOMO1 10 12.4 133.4 1214 28 1.3E+07 1.4E+07 1.2E+07 1.3E+07 1.6E+07 1.2E+07 405 Q6ZQI3 Malectin MLEC 3 17.9 32.3 291 27 1.3E+07 1.2E+07 1.3E+07 1.0E+07 1.3E+07 1.5E+07 Small nuclear ribonucleoprotein-associated 406 P27048 SNRPB 2 3.9 23.7 231 7 1.2E+07 7.2E+06 4.4E+06 0.0E+00 0.0E+00 0.0E+00 protein B 407 P17918 Proliferating cell nuclear antigen PCNA 3 14.9 28.8 261 32 1.2E+07 1.3E+07 1.9E+07 1.7E+07 1.3E+07 1.7E+07 408 O08709 Peroxiredoxin-6 PRDX6 6 34.8 24.9 224 10 1.2E+07 1.5E+07 9.9E+06 2.8E+07 2.7E+07 2.5E+07 Cytochrome b-c1 complex subunit Rieske, 409 Q9CR68 UQCRFS1 4 17.9 29.4 274 11 1.2E+07 1.1E+07 1.3E+07 1.6E+07 2.1E+07 2.6E+07 mitochondrial 410 O35682 Myeloid-associated differentiation marker MYADM 2 8.4 35.3 320 9 1.2E+07 7.8E+06 7.9E+06 0.0E+00 0.0E+00 0.0E+00 411 Q91WS0 CDGSH iron-sulfur domain-containing protein 1 CISD1 3 34.3 12.1 108 44 1.2E+07 7.5E+06 6.1E+06 2.7E+07 2.3E+07 2.8E+07 412 Q80UM7 Mannosyl-oligosaccharide glucosidase MOGS 7 10.6 91.8 834 23 1.2E+07 1.3E+07 1.3E+07 3.7E+06 4.2E+06 3.1E+06 413 P70296 Phosphatidylethanolamine-binding protein 1 PEBP1 4 38.5 20.8 187 11 1.2E+07 1.4E+07 1.4E+07 2.1E+07 1.2E+07 1.3E+07 414 P42125 Enoyl-CoA delta isomerase 1, mitochondrial ECI1 2 9.7 32.3 289 40 1.2E+07 1.1E+07 1.4E+07 0.0E+00 9.3E+06 9.9E+06 Calcium-binding mitochondrial carrier protein 415 Q9QXX4 SLC25A13 7 19.8 74.5 676 44 1.2E+07 8.7E+06 7.2E+06 1.4E+07 1.2E+07 9.2E+06 Aralar2 416 Q9CQ69 Cytochrome b-c1 complex subunit 8 UQCRQ 3 63.4 9.8 82 11 1.2E+07 0.0E+00 7.6E+06 0.0E+00 1.4E+07 1.1E+07 417 Q8JZU2 Tricarboxylate transport protein, mitochondrial SLC25A1 5 16.7 33.9 311 14 1.2E+07 1.0E+07 1.3E+07 2.5E+07 2.3E+07 2.3E+07 Immediate early response 3-interacting protein 418 Q9Y5U9 IER3IP1 2 34.1 9.0 82 14 1.2E+07 1.6E+07 1.5E+07 1.8E+07 1.5E+07 1.8E+07 1 419 Q99LP6 GrpE protein homolog 1, mitochondrial GRPEL1 5 26.3 24.3 217 18 1.1E+07 4.9E+06 5.8E+06 1.9E+07 5.4E+07 6.6E+07 420 Q8C7X2 ER membrane protein complex subunit 1 EMC1 13 17.2 111.6 997 33 1.1E+07 1.2E+07 8.8E+06 1.2E+07 1.1E+07 1.1E+07 Acyl-CoA dehydrogenase family member 9, 421 Q8JZN5 ACAD9 6 15.0 68.7 625 66 1.1E+07 1.3E+07 1.2E+07 9.1E+06 1.5E+07 1.7E+07 mitochondrial Lamina-associated polypeptide 2, isoforms 422 Q61029 TMPO 5 19.0 50.4 452 30 1.1E+07 1.7E+07 6.1E+06 4.7E+06 6.6E+06 5.0E+06 beta/delta/epsilon/gamma bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

NADH dehydrogenase [ubiquinone] 1 alpha 423 Q9DCJ5 NDUFA8 3 26.7 20.0 172 7 1.1E+07 7.9E+06 6.9E+06 8.5E+06 6.5E+06 7.4E+06 subcomplex subunit 8 424 Q05816 Fatty acid-binding protein, epidermal FABP5 3 30.4 15.1 135 20 1.1E+07 1.6E+07 1.4E+07 6.4E+07 1.8E+07 0.0E+00 425 Q99PV0 Pre-mRNA-processing-splicing factor 8 PRPF8 18 9.2 273.6 2335 76 1.1E+07 1.3E+07 1.4E+07 1.2E+07 1.2E+07 1.1E+07 426 P05622 Platelet-derived growth factor receptor beta PDGFRB 2 2.0 122.8 1098 3 1.1E+07 5.0E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 427 Q8K0D5 Elongation factor G, mitochondrial GFM1 12 19.4 83.5 751 28 1.1E+07 1.0E+07 1.2E+07 3.1E+07 2.0E+07 2.3E+07 428 P63276 40S ribosomal protein S17 RPS17 3 40.0 15.5 135 60 1.1E+07 1.2E+07 7.3E+06 9.1E+06 9.0E+06 1.2E+07 429 Q8BTM8 Filamin-A FLNA 13 6.5 281.2 2647 33 1.1E+07 1.1E+07 2.5E+07 1.5E+07 9.1E+06 2.4E+06 430 Q91W90 Thioredoxin domain-containing protein 5 TXNDC5 6 14.9 46.4 417 38 1.1E+07 1.1E+07 2.6E+07 1.0E+07 8.9E+06 1.2E+07 Procollagen-lysine,2-oxoglutarate 5- 431 Q9R0E2 PLOD1 8 15.7 83.6 728 50 1.1E+07 9.7E+06 1.1E+07 1.3E+07 8.6E+06 7.6E+06 dioxygenase 1 U5 small nuclear ribonucleoprotein 200 kDa 432 Q6P4T2 SNRNP200 18 11.1 244.5 2136 41 1.1E+07 1.1E+07 9.1E+06 1.2E+07 1.1E+07 1.1E+07 helicase 433 O35114 Lysosome membrane protein 2 SCARB2 4 10.9 54.0 478 14 1.1E+07 7.3E+06 4.3E+06 1.9E+07 1.3E+07 1.4E+07 434 Q9CQM2 ER lumen protein-retaining receptor 2 KDELR2 4 27.4 24.5 212 15 1.1E+07 5.4E+06 1.4E+07 0.0E+00 6.0E+06 1.4E+07 435 Q61543 Golgi apparatus protein 1 GLG1 5 4.9 133.7 1175 23 1.1E+07 1.2E+07 1.2E+07 3.8E+06 3.5E+06 3.1E+06 436 Q925I1 ATPase family AAA domain-containing protein 3 ATAD3 6 9.8 66.7 591 24 1.1E+07 8.5E+06 4.5E+06 1.3E+07 1.1E+07 1.2E+07 Long-chain specific acyl-CoA dehydrogenase, 437 P51174 ACADL 4 10.7 47.9 430 43 1.1E+07 1.2E+07 2.2E+07 3.6E+07 3.8E+07 1.4E+07 mitochondrial 438 P80318 T-complex protein 1 subunit gamma CCT3 6 15.0 60.6 545 23 1.1E+07 1.0E+07 1.5E+07 1.3E+07 9.3E+06 1.1E+07 439 Q60715 Prolyl 4-hydroxylase subunit alpha-1 P4HA1 8 19.9 60.9 534 105 1.0E+07 1.5E+07 2.8E+07 2.0E+07 1.5E+07 1.2E+07 Supplementary file 4A : (continued) 440 P17427 AP-2 complex subunit alpha-2 AP2A2 7 10.6 104.0 938 14 1.0E+07 6.7E+06 6.8E+06 3.8E+06 3.4E+06 3.8E+06 441 P59999 Actin-related protein 2/3 complex subunit 4 ARPC4 3 18.5 19.7 168 10 1.0E+07 9.6E+06 1.2E+07 1.1E+07 1.2E+07 1.2E+07 442 P09528 Ferritin heavy chain FTH1 3 17.0 21.1 182 11 1.0E+07 1.0E+07 1.1E+07 2.8E+07 1.3E+07 1.4E+07 443 Q9JKR6 Hypoxia up-regulated protein 1 HYOU1 10 13.0 111.2 999 103 1.0E+07 7.5E+06 1.4E+07 2.1E+07 1.9E+07 2.4E+07 444 P61027 Ras-related protein Rab-10 RAB10 2 20.5 22.5 200 29 1.0E+07 1.0E+07 0.0E+00 0.0E+00 7.8E+06 1.4E+07 445 Q64337 Sequestosome-1 SQSTM1 3 9.5 48.2 442 42 1.0E+07 6.8E+06 4.5E+06 1.6E+07 1.6E+07 1.6E+07 446 Q9EQH3 Vacuolar protein sorting-associated protein 35 VPS35 7 11.4 91.7 796 21 1.0E+07 7.3E+06 6.1E+06 4.7E+06 5.0E+06 4.5E+06 447 Q8R0X7 Sphingosine-1-phosphate lyase 1 SGPL1 3 7.7 63.7 568 16 9.7E+06 8.4E+06 1.3E+07 8.6E+06 9.0E+06 7.1E+06 448 P24369 Peptidyl-prolyl cis-trans isomerase B PPIB 4 22.2 23.7 216 36 9.7E+06 9.9E+06 3.2E+07 6.9E+06 5.1E+06 5.3E+06 449 P46460 Vesicle-fusing ATPase NSF 8 12.5 82.6 744 33 9.5E+06 1.5E+07 1.3E+07 2.6E+07 1.4E+07 1.4E+07 450 Q6S8J3 POTE ankyrin domain family member E POTEE 1 10.1 121.4 1075 2 9.4E+06 2.1E+07 1.2E+07 1.6E+07 0.0E+00 1.2E+07 451 P68254 14-3-3 protein theta YWHAQ 4 33.5 27.8 245 54 9.3E+06 1.3E+07 0.0E+00 1.6E+07 1.9E+07 1.4E+07 Guanine nucleotide-binding protein subunit beta- 452 P68040 GNB2L1 6 21.8 35.1 317 17 9.3E+06 1.8E+07 9.8E+06 6.4E+06 2.5E+07 2.6E+07 2-like 1 453 Q8K297 Procollagen galactosyltransferase 1 COLGALT1 5 9.1 71.1 617 13 9.2E+06 9.5E+06 1.2E+07 1.1E+07 1.3E+07 1.5E+07 454 P68510 14-3-3 protein eta YWHAH 4 29.7 28.2 246 53 9.2E+06 1.3E+07 9.8E+06 1.5E+07 2.0E+07 1.5E+07 455 Q9QY73 Transmembrane protein 59 TMEM59 2 7.7 36.3 323 4 9.0E+06 1.2E+07 1.2E+07 2.6E+07 1.5E+07 1.5E+07 456 Q922J9 Fatty acyl-CoA reductase 1 FAR1 6 20.0 59.4 515 65 8.9E+06 8.7E+06 9.7E+06 1.3E+07 1.2E+07 1.1E+07 457 P47915 60S ribosomal protein L29 RPL29 2 13.8 17.6 160 3 8.9E+06 1.1E+07 0.0E+00 5.5E+06 7.8E+06 0.0E+00 458 P08228 Superoxide dismutase [Cu-Zn] SOD1 3 23.4 15.9 154 9 8.8E+06 1.5E+07 1.2E+07 9.2E+07 2.9E+07 1.6E+08 459 P47755 F-actin-capping protein subunit alpha-2 CAPZA2 2 9.8 32.9 286 3 8.7E+06 7.7E+06 0.0E+00 8.8E+06 0.0E+00 5.8E+06 460 P57759 Endoplasmic reticulum resident protein 29 ERP29 3 11.8 28.8 262 14 8.6E+06 1.3E+07 2.1E+07 1.8E+07 1.1E+07 1.2E+07 461 Q9Z0R9 Fatty acid desaturase 2 FADS2 6 15.8 52.4 444 10 8.6E+06 7.3E+06 2.4E+06 4.1E+06 3.2E+06 2.7E+06 462 P35221 Catenin alpha-1 CTNNA1 8 14.3 100.1 906 41 8.5E+06 6.7E+06 8.8E+06 3.5E+06 4.7E+06 6.2E+06 Transmembrane emp24 domain-containing 463 Q9Y3B3 TMED7 2 10.3 25.2 224 7 8.5E+06 9.1E+06 1.7E+07 0.0E+00 5.7E+06 6.2E+06 protein 7 Dihydrolipoyllysine-residue succinyltransferase 464 Q9D2G2 component of 2-oxoglutarate dehydrogenase DLST 3 9.0 49.0 454 68 8.4E+06 5.7E+06 8.0E+06 1.4E+07 7.9E+06 8.2E+06 complex, mitochondrial 465 P30412 Peptidyl-prolyl cis-trans isomerase C PPIC 3 16.5 22.8 212 10 8.4E+06 6.2E+06 1.9E+07 7.7E+06 5.8E+06 6.4E+06 466 Q8VE37 Regulator of chromosome condensation RCC1 5 17.6 44.9 421 31 8.3E+06 9.3E+06 5.7E+06 8.1E+06 7.7E+06 7.8E+06 Sodium/potassium-transporting ATPase subunit 467 P97370 ATP1B3 2 11.2 31.8 278 7 8.2E+06 2.9E+06 6.0E+06 3.8E+06 3.7E+06 0.0E+00 beta-3 468 P80317 T-complex protein 1 subunit zeta CCT6A 5 18.8 58.0 531 13 8.2E+06 8.2E+06 4.3E+06 4.3E+06 5.8E+06 4.9E+06 469 Q9CZE3 Ras-related protein Rab-32 RAB32 3 15.7 25.1 223 7 8.2E+06 7.1E+06 6.5E+06 7.5E+06 0.0E+00 7.0E+06 470 P21107 Tropomyosin alpha-3 chain TPM3 2 11.2 33.0 285 6 8.2E+06 0.0E+00 9.2E+06 0.0E+00 0.0E+00 0.0E+00 471 Q60865 Caprin-1 CAPRIN1 5 9.9 78.2 707 37 8.2E+06 8.0E+06 3.3E+06 2.9E+06 4.7E+06 3.5E+06 NADH dehydrogenase [ubiquinone] 1 alpha 472 Q9ERS2 NDUFA13 2 13.2 16.9 144 2 8.1E+06 7.7E+06 0.0E+00 1.1E+07 0.0E+00 0.0E+00 subcomplex subunit 13 473 P18572 Basigin BSG 3 10.3 42.4 389 6 8.1E+06 4.4E+06 5.1E+06 1.3E+07 9.8E+06 7.5E+06 474 P17987 T-complex protein 1 subunit alpha TCP1 4 9.9 60.3 556 20 8.0E+06 1.3E+07 1.1E+07 1.1E+07 9.2E+06 8.8E+06 475 Q9NZ01 Very-long-chain enoyl-CoA reductase TECR 2 6.8 36.0 308 5 8.0E+06 1.1E+07 1.2E+07 6.6E+06 9.1E+06 0.0E+00 476 Q61171 Peroxiredoxin-2 PRDX2 4 27.8 21.8 198 12 7.9E+06 1.1E+07 1.3E+07 1.5E+07 8.7E+06 9.7E+06 Bifunctional methylenetetrahydrofolate 477 P18155 MTHFD2 2 10.0 37.9 350 3 7.9E+06 4.9E+06 5.4E+06 3.0E+06 0.0E+00 0.0E+00 dehydrogenase/cyclohydrolase, mitochondrial 478 O09005 Sphingolipid delta(4)-desaturase DES1 DEGS1 2 10.2 38.2 323 10 7.9E+06 6.8E+06 5.8E+06 7.0E+06 1.6E+07 9.6E+06 116 kDa U5 small nuclear ribonucleoprotein 479 O08810 EFTUD2 9 13.4 109.4 971 26 7.9E+06 7.2E+06 7.0E+06 6.9E+06 5.6E+06 4.6E+06 component 480 Q6ZWQ7 Signal peptidase complex subunit 3 SPCS3 2 11.7 20.3 180 12 7.8E+06 4.3E+06 9.8E+06 2.4E+06 2.2E+06 0.0E+00 481 P70349 Histidine triad nucleotide-binding protein 1 HINT1 2 27.0 13.8 126 8 7.7E+06 1.1E+07 1.1E+07 1.9E+07 1.4E+07 0.0E+00 482 Q9DB05 Alpha-soluble NSF attachment protein NAPA 2 9.2 33.2 295 23 7.7E+06 7.0E+06 0.0E+00 4.9E+06 5.2E+06 6.6E+06 483 P45376 Aldose reductase AKR1B1 6 21.5 35.7 316 28 7.7E+06 7.5E+06 1.1E+07 6.7E+07 4.0E+07 3.8E+07 484 Q08211 ATP-dependent RNA helicase A DHX9 1 18.0 141.0 1270 3 7.6E+06 1.5E+07 9.6E+06 2.0E+07 1.4E+07 1.5E+07 485 Q71U36 Tubulin alpha-1A chain TUBA1A 2 64.5 50.1 451 24 7.6E+06 9.8E+06 1.0E+07 6.4E+06 0.0E+00 0.0E+00 486 Q8K4Z3 NAD(P)H-hydrate epimerase APOA1BP 2 10.6 31.0 282 10 7.6E+06 6.7E+06 9.8E+06 7.7E+06 8.0E+06 0.0E+00 487 Q9CQN1 Heat shock protein 75 kDa, mitochondrial TRAP1 5 11.2 80.2 706 23 7.6E+06 7.2E+06 7.4E+06 9.2E+06 1.1E+07 1.2E+07 Prolow-density lipoprotein receptor-related 488 Q91ZX7 LRP1 12 3.8 504.7 4545 51 7.5E+06 1.4E+07 1.3E+07 3.5E+06 0.0E+00 3.4E+06 protein 1 489 Q9Y5S9 RNA-binding protein 8A RBM8A 3 23.0 19.9 174 4 7.5E+06 7.8E+06 8.3E+06 1.6E+07 8.8E+06 9.5E+06 490 Q9JIK9 28S ribosomal protein S34, mitochondrial MRPS34 2 7.3 25.8 218 3 7.3E+06 7.1E+06 6.6E+06 6.6E+06 7.0E+06 7.3E+06 491 Q6P5E4 UDP-glucose:glycoprotein glucosyltransferase 1 UGGT1 11 10.1 176.4 1551 39 7.3E+06 8.1E+06 1.5E+07 1.9E+07 1.4E+07 1.4E+07 492 P56537 Eukaryotic translation initiation factor 6 EIF6 3 24.5 26.6 245 10 7.1E+06 6.4E+06 7.1E+06 7.3E+06 6.8E+06 9.2E+06 493 P97807 Fumarate hydratase, mitochondrial FH 5 17.2 54.4 507 34 7.0E+06 5.0E+06 3.8E+06 7.4E+06 9.2E+06 9.8E+06 494 Q8CF66 Ragulator complex protein LAMTOR4 LAMTOR4 1 10.1 10.7 99 9 6.9E+06 1.0E+07 1.0E+07 1.0E+07 9.7E+06 0.0E+00 Insulin-like growth factor 2 mRNA-binding 495 Q9NZI8 IGF2BP1 4 8.7 63.5 577 11 6.9E+06 6.8E+06 3.6E+06 8.5E+06 7.4E+06 6.5E+06 protein 1 496 P14152 Malate dehydrogenase, cytoplasmic MDH1 3 10.8 36.5 334 5 6.8E+06 0.0E+00 1.1E+07 1.6E+07 0.0E+00 0.0E+00 497 Q9D6U8 Protein FAM162A FAM162A 3 27.1 17.7 155 6 6.8E+06 6.7E+06 5.7E+06 2.3E+07 0.0E+00 0.0E+00 498 Q99J19 Small integral membrane protein 11 SMIM11 2 49.1 6.3 55 8 6.8E+06 5.5E+06 8.1E+06 6.4E+06 6.5E+06 8.4E+06 Succinyl-CoA ligase [GDP-forming] subunit 499 Q9Z2I8 SUCLG2 3 12.5 46.8 433 12 6.7E+06 5.9E+06 5.1E+06 0.0E+00 0.0E+00 0.0E+00 beta, mitochondrial 500 Q99JB2 Stomatin-like protein 2, mitochondrial STOML2 2 9.1 38.4 353 8 6.6E+06 6.3E+06 5.7E+06 6.1E+06 3.9E+06 4.9E+06 501 P24270 Catalase CAT 5 15.7 59.8 527 18 6.6E+06 6.0E+06 5.3E+06 5.5E+06 4.4E+06 4.9E+06 502 L0R6Q1 SLC35A4 2 18.4 11.1 103 2 6.5E+06 8.5E+06 1.0E+07 2.4E+07 1.1E+07 6.2E+06 503 Q08943 FACT complex subunit SSRP1 SSRP1 6 13.0 80.9 708 74 6.5E+06 8.6E+06 8.0E+06 9.1E+06 5.6E+06 9.7E+06 504 Q9CQF9 Prenylcysteine oxidase PCYOX1 4 13.9 56.5 505 7 6.4E+06 6.3E+06 5.1E+06 4.3E+06 5.3E+06 0.0E+00 505 Q9QYR9 Acyl-coenzyme A thioesterase 2, mitochondrial ACOT2 5 15.0 49.7 453 12 6.4E+06 4.5E+06 6.0E+06 3.0E+06 0.0E+00 0.0E+00 506 P17439 Glucosylceramidase GBA 4 9.9 57.6 515 20 6.4E+06 4.3E+06 7.5E+06 6.3E+06 7.2E+06 5.7E+06 507 O35639 Annexin A3 ANXA3 4 16.1 36.4 323 14 6.4E+06 1.6E+07 1.4E+07 1.3E+07 7.1E+06 9.1E+06 508 Q8CCS6 Polyadenylate-binding protein 2 PABPN1 2 8.9 32.3 302 3 6.3E+06 7.4E+06 7.7E+06 8.8E+06 0.0E+00 7.4E+06 509 P14901 Heme oxygenase 1 HMOX1 2 9.7 32.9 289 6 6.2E+06 5.6E+06 5.2E+06 1.8E+07 7.7E+06 0.0E+00 510 P32020 Non-specific lipid-transfer protein SCP2 3 5.3 59.1 547 20 6.2E+06 6.0E+06 8.4E+06 1.2E+07 1.4E+07 1.7E+07 511 P80315 T-complex protein 1 subunit delta CCT4 4 10.0 58.1 539 9 6.2E+06 7.7E+06 4.0E+06 8.7E+06 9.8E+06 7.7E+06 512 Q3U9G9 Lamin-B receptor LBR 4 10.7 71.4 626 16 6.1E+06 4.5E+06 5.2E+06 4.0E+06 8.3E+06 7.3E+06 513 P32067 Lupus La protein homolog SSB 4 13.3 47.8 415 31 6.1E+06 3.6E+06 3.5E+06 3.5E+06 5.0E+06 5.8E+06 514 Q16799 Reticulon-1 RTN1 2 2.1 83.6 776 2 6.0E+06 4.3E+06 7.1E+06 1.4E+07 2.4E+07 2.8E+07 515 Q99PL5 Ribosome-binding protein 1 RRBP1 3 2.7 172.9 1605 21 6.0E+06 0.0E+00 0.0E+00 2.6E+06 2.3E+06 0.0E+00 516 Q9NR31 GTP-binding protein SAR1a SAR1A 2 11.6 22.4 198 9 6.0E+06 6.1E+06 6.1E+06 1.5E+07 0.0E+00 2.7E+06 517 Q8CIE6 Coatomer subunit alpha COPA 5 4.6 138.4 1224 27 6.0E+06 6.5E+06 5.3E+06 6.6E+06 4.3E+06 4.5E+06 518 Q9Y224 UPF0568 protein C14orf166 C14ORF166 4 20.9 28.1 244 11 6.0E+06 7.5E+06 0.0E+00 0.0E+00 0.0E+00 5.5E+06 519 Q99J56 Derlin-1 DERL1 3 13.1 28.8 251 21 5.9E+06 4.4E+06 5.5E+06 4.4E+06 1.1E+07 9.0E+06 520 Q9CQW0 ER membrane protein complex subunit 6 EMC6 2 20.0 12.0 110 5 5.9E+06 8.6E+06 8.0E+06 8.7E+06 8.1E+06 9.6E+06 521 Q8BLN5 Lanosterol synthase LSS 5 8.0 83.1 733 13 5.7E+06 6.6E+06 8.5E+06 6.0E+06 5.8E+06 5.8E+06 522 Q9CZR8 Elongation factor Ts, mitochondrial TSFM 2 13.6 35.3 324 14 5.6E+06 0.0E+00 9.2E+06 1.1E+07 6.5E+06 1.1E+07 523 Q99JY0 Trifunctional enzyme subunit beta, mitochondrial HADHB 6 16.4 51.4 475 21 5.6E+06 6.3E+06 8.0E+06 2.2E+07 1.5E+07 1.3E+07 Short-chain specific acyl-CoA dehydrogenase, 524 Q07417 ACADS 4 14.6 44.9 412 48 5.5E+06 5.0E+06 5.5E+06 5.5E+06 6.8E+06 8.3E+06 mitochondrial 525 O75165 DnaJ homolog subfamily C member 13 DNAJC13 8 3.9 254.4 2243 16 5.4E+06 4.0E+06 3.7E+06 2.2E+06 1.3E+06 2.8E+06 526 P43406 Integrin alpha-V ITGAV 4 4.7 115.4 1044 15 5.3E+06 5.1E+06 3.9E+06 2.7E+06 0.0E+00 0.0E+00 527 Q9WV32 Actin-related protein 2/3 complex subunit 1B ARPC1B 2 7.3 41.1 372 3 5.3E+06 0.0E+00 0.0E+00 0.0E+00 6.7E+06 0.0E+00 528 P12236 ADP/ATP translocase 3 SLC25A6 2 45.3 32.9 298 6 5.3E+06 7.0E+06 8.4E+06 1.1E+07 2.5E+07 0.0E+00 529 Q9R0P3 S-formylglutathione hydrolase ESD 2 13.8 31.3 282 5 5.3E+06 6.8E+06 6.9E+06 8.6E+06 4.9E+06 8.6E+06 530 O54879 High mobility group protein B3 HMGB3 2 14.5 23.0 200 6 5.3E+06 8.5E+06 1.2E+07 4.4E+06 5.1E+06 4.3E+06 531 P29533 Vascular cell adhesion protein 1 VCAM1 3 5.0 81.3 739 21 5.2E+06 4.4E+06 3.0E+06 0.0E+00 0.0E+00 0.0E+00 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

532 Q9D0F3 Protein ERGIC-53 LMAN1 3 8.5 57.8 517 15 5.2E+06 1.1E+07 6.0E+06 3.9E+06 0.0E+00 3.7E+06 533 Q61024 Asparagine synthetase [glutamine-hydrolyzing] ASNS 5 9.8 64.3 561 13 5.2E+06 5.8E+06 7.2E+06 3.8E+06 3.5E+06 3.5E+06 534 Q9D024 Coiled-coil domain-containing protein 47 CCDC47 2 5.4 55.8 483 3 5.2E+06 4.0E+06 3.2E+06 3.8E+06 4.2E+06 0.0E+00 535 P62996 Transformer-2 protein homolog beta TRA2B 4 20.8 33.7 288 38 5.1E+06 1.3E+07 4.7E+06 1.1E+07 7.2E+06 7.4E+06 Transmembrane emp24 domain-containing 536 Q9Y3A6 TMED5 2 9.2 26.0 229 41 5.0E+06 3.5E+06 4.0E+06 8.5E+06 5.3E+06 5.2E+06 protein 5 537 P80314 T-complex protein 1 subunit beta CCT2 6 17.8 57.5 535 28 5.0E+06 4.0E+06 4.6E+06 5.8E+06 7.2E+06 6.3E+06 538 Q9CZW5 Mitochondrial import receptor subunit TOM70 TOMM70A 5 11.5 67.6 611 9 4.9E+06 1.5E+06 3.6E+06 3.4E+06 4.8E+06 4.7E+06 539 O94905 Erlin-2 ERLIN2 3 12.1 37.8 339 22 4.8E+06 4.4E+06 5.9E+06 1.0E+07 8.8E+06 5.8E+06 540 P63028 Translationally-controlled tumor protein TPT1 1 8.1 19.5 172 3 4.8E+06 0.0E+00 5.5E+06 5.0E+06 4.0E+06 4.5E+06 541 P58742 Aladin AAAS 4 10.1 59.4 546 17 4.7E+06 3.0E+06 4.1E+06 2.0E+06 2.3E+06 1.4E+06 542 Q99KP6 Pre-mRNA-processing factor 19 PRPF19 3 7.5 55.2 504 11 4.7E+06 5.0E+06 8.1E+06 0.0E+00 2.0E+06 0.0E+00 543 Q8K411 Presequence protease, mitochondrial PITRM1 7 9.7 117.4 1036 14 4.7E+06 3.1E+06 1.4E+06 3.5E+06 2.5E+06 0.0E+00 544 Q61553 Fascin FSCN1 4 12.6 54.5 493 9 4.6E+06 0.0E+00 5.4E+06 0.0E+00 0.0E+00 0.0E+00 SWI/SNF-related matrix-associated actin- 545 Q91ZW3 dependent regulator of chromatin subfamily A SMARCA5 4 3.9 121.6 1051 9 4.6E+06 5.5E+06 4.3E+06 5.0E+06 0.0E+00 3.3E+06 member 5 Serine/threonine-protein phosphatase 2A 546 P67775 PPP2CA 2 11.7 35.6 309 8 4.4E+06 3.9E+06 4.9E+06 5.3E+06 0.0E+00 0.0E+00 catalytic subunit alpha isoform 547 Q9CPY7 Cytosol aminopeptidase LAP3 5 12.9 56.1 519 24 4.3E+06 5.0E+06 4.4E+06 7.1E+06 6.1E+06 5.2E+06 548 Q9CRD0 OCIA domain-containing protein 1 OCIAD1 3 19.4 27.6 247 9 4.3E+06 5.3E+06 4.3E+06 8.8E+06 1.0E+07 5.0E+06 549 Q9WVA4 Transgelin-2 TAGLN2 3 21.6 22.4 199 73 4.2E+06 4.7E+06 0.0E+00 1.1E+07 7.1E+06 7.1E+06 550 Q8BKE6 Cytochrome P450 20A1 CYP20A1 3 12.3 52.1 462 7 4.2E+06 2.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 551 P99029 Peroxiredoxin-5, mitochondrial PRDX5 4 24.8 21.9 210 12 4.1E+06 3.0E+06 4.5E+06 0.0E+00 2.8E+06 3.7E+06 552 Q9D6K8 FUN14 domain-containing protein 2 FUNDC2 3 29.8 16.6 151 6 4.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 Supplementary file 4A : (continued) 553 Q99PL7 Acyl-CoA desaturase 2 SCD3 2 10.6 41.4 359 3 4.0E+06 3.5E+06 2.2E+06 4.5E+06 7.7E+06 5.9E+06 554 P11688 Integrin alpha-5 ITGA5 3 3.2 115.0 1053 6 4.0E+06 4.2E+06 4.6E+06 3.0E+06 0.0E+00 2.6E+06 555 Q8BP47 Asparagine--tRNA ligase, cytoplasmic NARS 3 6.1 64.3 559 10 4.0E+06 5.4E+06 4.7E+06 3.1E+06 0.0E+00 0.0E+00 556 Q02053 Ubiquitin-like modifier-activating enzyme 1 UBA1 4 5.9 117.8 1058 15 4.0E+06 3.2E+06 0.0E+00 5.0E+06 5.1E+06 5.7E+06 557 P48024 Eukaryotic translation initiation factor 1 EIF1 3 40.7 12.7 113 34 4.0E+06 4.1E+06 6.2E+06 6.0E+06 7.7E+06 1.1E+07 558 Q9JHI5 Isovaleryl-CoA dehydrogenase, mitochondrial IVD 3 9.2 46.3 424 22 4.0E+06 4.5E+06 4.6E+06 4.8E+06 3.4E+06 0.0E+00 Lamina-associated polypeptide 2, isoforms 559 Q61033 TMPO 2 12.0 75.2 693 3 3.9E+06 3.4E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 alpha/zeta NADH dehydrogenase [ubiquinone] 1 alpha 560 Q9DC69 NDUFA9 6 22.0 42.5 377 12 3.9E+06 5.2E+06 3.0E+06 2.9E+06 6.0E+06 4.9E+06 subcomplex subunit 9, mitochondrial 561 P50990 T-complex protein 1 subunit theta CCT8 3 6.0 59.6 548 10 3.9E+06 0.0E+00 3.8E+06 4.7E+06 5.1E+06 0.0E+00 562 P17480 Nucleolar transcription factor 1 UBTF 2 4.1 89.4 764 5 3.8E+06 4.1E+06 3.1E+06 2.7E+06 3.5E+06 3.1E+06 563 P08003 Protein disulfide-isomerase A4 PDIA4 10 17.9 72.0 638 28 3.8E+06 7.9E+06 3.9E+07 1.7E+07 1.6E+07 1.9E+07 564 Q3U7R1 Extended synaptotagmin-1 ESYT1 6 9.4 121.6 1092 14 3.8E+06 8.0E+06 6.1E+06 2.3E+06 0.0E+00 1.9E+06 565 Q8BIJ6 Isoleucine--tRNA ligase, mitochondrial IARS2 7 9.0 112.8 1012 27 3.8E+06 3.1E+06 3.6E+06 7.6E+06 5.9E+06 7.0E+06 566 O43390 Heterogeneous nuclear ribonucleoprotein R HNRNPR 3 7.7 70.9 633 32 3.8E+06 3.2E+06 4.0E+06 4.8E+06 3.7E+06 3.5E+06 Succinyl-CoA ligase [ADP-forming] subunit 567 Q9Z2I9 SUCLA2 2 7.1 50.1 463 5 3.8E+06 2.3E+06 2.1E+06 0.0E+00 0.0E+00 0.0E+00 beta, mitochondrial 568 Q61699 Heat shock protein 105 kDa HSPH1 6 8.9 96.4 858 12 3.8E+06 3.7E+06 3.9E+06 7.2E+06 6.0E+06 8.0E+06 569 Q61595 Kinectin KTN1 5 5.7 152.6 1327 20 3.8E+06 4.7E+06 3.6E+06 3.7E+06 0.0E+00 2.8E+06 570 Q6PD26 GPI transamidase component PIG-S PIGS 3 8.3 61.7 555 29 3.7E+06 5.2E+06 5.0E+06 2.8E+06 7.5E+06 8.4E+06 571 Q9JLR9 HIG1 domain family member 1A, mitochondrial HIGD1A 2 42.1 10.4 95 115 3.7E+06 3.0E+06 3.4E+06 0.0E+00 1.2E+07 2.2E+07 572 Q64314 Hematopoietic progenitor cell antigen CD34 CD34 2 5.0 41.0 382 5 3.6E+06 0.0E+00 0.0E+00 3.2E+06 0.0E+00 3.7E+06 573 Q61598 Rab GDP dissociation inhibitor beta GDI2 5 15.5 50.5 445 17 3.6E+06 3.5E+06 1.7E+06 0.0E+00 4.9E+06 3.5E+06 574 Q920E5 Farnesyl pyrophosphate synthase FDPS 2 7.4 40.6 353 34 3.6E+06 4.9E+06 8.3E+06 8.2E+06 5.5E+06 0.0E+00 575 Q9CPX8 Cytochrome b-c1 complex subunit 10 UQCR11 1 21.4 6.5 56 2 3.6E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 Dephospho-CoA kinase domain-containing 576 Q8WVC6 DCAKD 2 6.1 26.6 231 18 3.6E+06 4.4E+06 3.9E+06 0.0E+00 0.0E+00 0.0E+00 protein 577 Q99NB9 Splicing factor 3B subunit 1 SF3B1 4 4.4 145.8 1304 7 3.6E+06 4.2E+06 3.9E+06 4.6E+06 2.6E+06 3.6E+06 578 Q92973 Transportin-1 TNPO1 6 7.3 102.4 898 10 3.6E+06 2.7E+06 2.4E+06 2.2E+06 3.7E+06 3.7E+06 579 O94925 Glutaminase kidney isoform, mitochondrial GLS 4 7.2 73.5 669 5 3.5E+06 3.9E+06 6.2E+06 3.0E+06 2.9E+06 3.1E+06 580 P19096 Fatty acid synthase FASN 10 5.4 272.4 2504 19 3.4E+06 3.8E+06 4.7E+06 7.1E+06 6.8E+06 4.7E+06 581 Q02248 Catenin beta-1 CTNNB1 3 5.8 85.5 781 22 3.4E+06 3.1E+06 2.8E+06 2.4E+06 2.2E+06 2.1E+06 582 P57716 Nicastrin NCSTN 5 7.9 78.5 708 12 3.4E+06 6.2E+06 4.4E+06 2.9E+06 6.5E+06 6.5E+06 583 P11103 Poly [ADP-ribose] polymerase 1 PARP1 2 2.6 113.1 1013 6 3.4E+06 0.0E+00 0.0E+00 1.4E+06 0.0E+00 1.1E+06 584 Q9D5T0 ATPase family AAA domain-containing protein 1 ATAD1 3 11.1 40.7 361 14 3.4E+06 5.0E+06 3.5E+06 4.7E+06 4.9E+06 3.9E+06 585 P0DN34 2 14.0 7.0 57 2 3.3E+06 3.1E+06 0.0E+00 0.0E+00 5.6E+06 3.9E+06 586 Q6ZQL4 WD repeat-containing protein 43 WDR43 4 7.4 75.4 677 15 3.3E+06 4.0E+06 6.0E+06 1.0E+07 3.6E+06 4.4E+06 587 Q9Z1N5 Spliceosome RNA helicase Ddx39b DDX39B 3 9.6 49.0 428 14 3.3E+06 4.0E+06 3.8E+06 4.1E+06 4.0E+06 3.5E+06 588 Q91YH5 Atlastin-3 ATL3 5 14.2 60.6 541 15 3.3E+06 3.4E+06 2.5E+06 3.9E+06 3.4E+06 2.3E+06 589 P22437 Prostaglandin G/H synthase 1 PTGS1 3 6.8 69.0 602 25 3.3E+06 3.7E+06 5.0E+06 3.8E+06 4.2E+06 3.3E+06 590 Q8CI59 Metalloreductase STEAP3 STEAP3 6 16.2 54.7 488 13 3.2E+06 3.1E+06 3.0E+06 7.6E+06 1.3E+07 1.0E+07 591 P80316 T-complex protein 1 subunit epsilon CCT5 3 9.6 59.6 541 29 3.2E+06 4.2E+06 2.9E+06 0.0E+00 4.6E+06 3.6E+06 592 Q99P88 Nuclear pore complex protein Nup155 NUP155 3 3.2 155.1 1391 6 3.2E+06 2.1E+06 1.7E+06 1.9E+06 0.0E+00 2.4E+06 593 Q9D8M4 60S ribosomal protein L7-like 1 RPL7L1 3 17.1 28.5 246 6 3.2E+06 5.1E+06 6.8E+06 2.1E+06 2.8E+06 2.8E+06 Sorting and assembly machinery component 50 594 Q8BGH2 SAMM50 3 7.0 51.9 469 8 3.2E+06 3.3E+06 4.8E+06 3.8E+06 3.5E+06 3.0E+06 homolog 595 Q8VE22 28S ribosomal protein S23, mitochondrial MRPS23 2 11.3 20.3 177 5 3.2E+06 2.6E+06 2.9E+06 2.1E+06 2.9E+06 3.0E+06 2-amino-3-ketobutyrate coenzyme A ligase, 596 O88986 GCAT 3 12.7 44.9 416 15 3.2E+06 3.8E+06 6.8E+06 0.0E+00 3.8E+06 4.1E+06 mitochondrial 597 Q9ESW4 Acylglycerol kinase, mitochondrial AGK 1 5.9 47.0 421 2 3.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 598 Q91VR5 ATP-dependent RNA helicase DDX1 DDX1 4 8.0 82.5 740 7 3.1E+06 4.2E+06 2.8E+06 2.2E+06 2.5E+06 2.5E+06 599 Q921E2 Ras-related protein Rab-31 RAB31 4 25.3 21.3 194 15 3.1E+06 0.0E+00 0.0E+00 1.1E+07 5.7E+06 9.7E+06 600 Q9WUR9 Adenylate kinase 4, mitochondrial AK4 2 10.8 25.1 223 4 3.0E+06 2.7E+06 2.9E+06 6.0E+06 8.4E+06 6.6E+06 601 Q9EP69 Phosphatidylinositide phosphatase SAC1 SACM1L 3 6.0 66.9 587 11 3.0E+06 2.9E+06 3.1E+06 2.9E+06 4.6E+06 3.7E+06 602 P16332 Methylmalonyl-CoA mutase, mitochondrial MUT 4 6.3 82.8 748 10 3.0E+06 3.0E+06 3.5E+06 8.1E+06 3.7E+06 3.3E+06 603 P28656 Nucleosome assembly protein 1-like 1 NAP1L1 2 7.2 45.3 391 11 3.0E+06 3.9E+06 3.0E+06 6.2E+06 4.4E+06 1.5E+06 604 P17710 Hexokinase-1 HK1 7 8.6 108.3 974 24 3.0E+06 0.0E+00 3.0E+06 6.7E+06 3.8E+06 9.4E+06 605 Q9NVJ2 ADP-ribosylation factor-like protein 8B ARL8B 2 12.9 21.5 186 3 3.0E+06 4.3E+06 2.9E+06 0.0E+00 2.7E+06 3.3E+06 606 Q920A5 Retinoid-inducible serine carboxypeptidase SCPEP1 3 9.3 51.0 452 32 3.0E+06 4.0E+06 4.1E+06 5.0E+06 5.2E+06 5.5E+06 607 Q8C7K6 Prenylcysteine oxidase-like PCYOX1L 2 7.1 54.9 495 8 2.9E+06 2.7E+06 1.8E+06 2.2E+06 2.3E+06 2.0E+06 608 Q99JY9 Actin-related protein 3 ACTR3 3 12.7 47.4 418 18 2.9E+06 3.7E+06 3.1E+06 3.5E+06 2.4E+06 3.0E+06 609 P06733 Alpha-enolase ENO1 2 38.7 47.2 434 3 2.8E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 610 O88207 Collagen alpha-1(V) chain COL5A1 3 2.7 183.7 1838 4 2.7E+06 3.6E+06 4.4E+06 0.0E+00 0.0E+00 0.0E+00 611 Q61545 RNA-binding protein EWS EWSR1 1 2.1 68.5 655 4 2.7E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 612 Q64511 DNA topoisomerase 2-beta TOP2B 2 5.1 181.9 1612 4 2.7E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 613 Q9UGP8 Translocation protein SEC63 homolog SEC63 2 3.2 88.0 760 3 2.7E+06 3.2E+06 3.0E+06 2.0E+06 3.8E+06 3.7E+06 614 Q9R0U0 Serine/arginine-rich splicing factor 10 SRSF10 2 10.7 31.3 262 2 2.7E+06 0.0E+00 0.0E+00 2.3E+06 0.0E+00 0.0E+00 615 Q8BLF1 Neutral cholesterol ester hydrolase 1 NCEH1 8 31.1 45.7 408 28 2.6E+06 1.8E+06 1.8E+06 5.0E+06 2.4E+07 2.0E+07 616 Q9ER88 28S ribosomal protein S29, mitochondrial DAP3 4 15.9 44.7 391 13 2.6E+06 2.9E+06 3.2E+06 0.0E+00 3.5E+06 3.8E+06 U3 small nucleolar RNA-associated protein 15 617 Q8C7V3 UTP15 2 3.2 59.4 528 4 2.6E+06 1.9E+06 1.6E+06 1.7E+06 2.3E+06 1.6E+06 homolog 618 P53986 Monocarboxylate transporter 1 SLC16A1 3 6.5 53.3 493 13 2.6E+06 3.0E+06 2.7E+06 5.5E+06 6.6E+06 2.5E+06 619 Q64310 Surfeit locus protein 4 SURF4 3 17.5 30.4 269 26 2.6E+06 4.9E+06 5.6E+06 0.0E+00 3.3E+06 3.9E+06 620 Q8R5J9 PRA1 family protein 3 ARL6IP5 1 5.9 21.6 188 2 2.6E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 Guanine nucleotide-binding protein G(s) subunit 621 P63094 GNAS 3 12.9 45.7 394 15 2.5E+06 2.7E+06 2.0E+06 2.4E+06 1.9E+06 2.5E+06 alpha isoforms short 622 Q80W54 CAAX prenyl protease 1 homolog ZMPSTE24 2 6.1 54.7 475 4 2.5E+06 0.0E+00 2.7E+06 0.0E+00 7.7E+06 0.0E+00 CDP-diacylglycerol--inositol 3- 623 Q8VDP6 CDIPT 2 12.2 23.6 213 6 2.5E+06 1.8E+06 3.9E+06 2.6E+06 6.4E+06 5.6E+06 phosphatidyltransferase H-2 class I histocompatibility antigen, Q8 alpha 624 P14430 H2-Q8 2 5.5 37.4 326 2 2.4E+06 1.8E+06 2.1E+06 0.0E+00 0.0E+00 0.0E+00 chain 625 Q9DCL9 Multifunctional protein ADE2 PAICS 5 20.7 47.0 425 27 2.4E+06 3.5E+06 2.9E+06 0.0E+00 0.0E+00 2.1E+06 626 Q96CW1 AP-2 complex subunit mu AP2M1 2 4.1 49.7 435 2 2.4E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 627 Q9UIQ6 Leucyl-cystinyl aminopeptidase LNPEP 3 4.0 117.4 1025 26 2.4E+06 3.3E+06 3.0E+06 2.5E+06 3.2E+06 2.5E+06 628 Q62470 Integrin alpha-3 ITGA3 2 2.5 116.7 1053 5 2.3E+06 2.7E+06 2.1E+06 1.8E+06 2.2E+06 1.8E+06 UDP-N-acetylhexosamine pyrophosphorylase- 629 Q3TW96 UAP1L1 3 7.7 56.6 507 16 2.3E+06 2.5E+06 1.7E+06 5.6E+06 6.6E+06 6.0E+06 like protein 1 630 Q8BRF7 Sec1 family domain-containing protein 1 SCFD1 3 7.4 72.3 639 6 2.3E+06 1.8E+06 1.8E+06 2.0E+06 1.9E+06 1.8E+06 631 P52019 Squalene monooxygenase SQLE 2 4.7 63.8 572 5 2.2E+06 1.7E+06 1.0E+06 0.0E+00 1.5E+06 0.0E+00 632 Q9D1Q6 Endoplasmic reticulum resident protein 44 ERP44 2 7.6 46.9 406 3 2.2E+06 0.0E+00 2.3E+06 0.0E+00 0.0E+00 0.0E+00 633 P10649 Glutathione S-transferase Mu 1 GSTM1 2 15.1 26.0 218 4 2.2E+06 0.0E+00 0.0E+00 2.7E+06 2.8E+06 3.8E+06 Signal recognition particle receptor subunit 634 Q9DBG7 SRPR 4 10.5 69.6 636 11 2.2E+06 2.4E+06 1.6E+06 0.0E+00 0.0E+00 0.0E+00 alpha 635 Q5SYD0 Unconventional myosin-Id MYO1D 3 3.7 116.1 1006 9 2.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 636 Q9R112 Sulfide:quinone oxidoreductase, mitochondrial SQRDL 3 9.3 50.3 450 15 2.1E+06 0.0E+00 0.0E+00 2.1E+06 0.0E+00 0.0E+00 637 P13864 DNA (cytosine-5)-methyltransferase 1 DNMT1 2 2.0 183.2 1620 5 2.1E+06 5.4E+06 0.0E+00 0.0E+00 1.5E+06 0.0E+00 Cation-dependent mannose-6-phosphate 638 P24668 M6PR 1 6.5 31.2 278 19 2.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 receptor Very-long-chain (3R)-3-hydroxyacyl-CoA 639 Q9D3B1 HACD2 1 3.9 28.4 254 3 2.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 dehydratase 2 640 Q9ERD7 Tubulin beta-3 chain TUBB3 1 25.6 50.4 450 2 2.0E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Dolichyl-diphosphooligosaccharide--protein 641 P46978 STT3A 2 3.1 80.6 705 6 2.0E+06 3.1E+06 3.2E+06 3.3E+06 3.1E+06 0.0E+00 glycosyltransferase subunit STT3A NADH dehydrogenase [ubiquinone] 1 alpha 642 Q99LC3 NDUFA10 2 9.3 40.6 355 6 2.0E+06 4.0E+06 2.5E+06 0.0E+00 2.9E+06 3.7E+06 subcomplex subunit 10, mitochondrial 643 Q9D2R0 Acetoacetyl-CoA synthetase AACS 2 3.0 75.2 672 2 2.0E+06 1.6E+06 1.8E+06 0.0E+00 1.0E+06 1.9E+06 644 Q8BFR4 N-acetylglucosamine-6-sulfatase GNS 2 4.6 61.2 544 3 2.0E+06 1.7E+06 1.7E+06 0.0E+00 0.0E+00 1.4E+06 645 P29317 Ephrin type-A receptor 2 EPHA2 2 2.2 108.3 976 5 1.9E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 646 Q91WQ3 Tyrosine--tRNA ligase, cytoplasmic YARS 3 8.5 59.1 528 5 1.9E+06 2.3E+06 2.6E+06 0.0E+00 1.8E+06 0.0E+00 647 Q9NZN4 EH domain-containing protein 2 EHD2 3 7.2 61.2 543 5 1.9E+06 2.2E+06 1.6E+06 0.0E+00 1.6E+06 0.0E+00 648 Q8BHB4 WD repeat-containing protein 3 WDR3 2 2.5 105.8 942 7 1.9E+06 1.4E+06 0.0E+00 1.2E+06 0.0E+00 0.0E+00 649 Q9DCZ4 Apolipoprotein O APOO 2 12.6 22.6 198 5 1.8E+06 0.0E+00 2.1E+06 5.5E+06 2.3E+06 0.0E+00 Lipoamide acyltransferase component of 650 P53395 branched-chain alpha-keto acid dehydrogenase DBT 4 10.8 53.2 482 13 1.8E+06 1.3E+06 1.2E+06 0.0E+00 1.0E+06 1.0E+06 complex, mitochondrial 651 Q8WUM4 Programmed cell death 6-interacting protein PDCD6IP 2 3.2 96.0 868 13 1.8E+06 0.0E+00 7.2E+05 5.1E+05 0.0E+00 0.0E+00

652 P54823 Probable ATP-dependent RNA helicase DDX6 DDX6 2 5.4 54.2 483 7 1.8E+06 1.5E+06 4.9E+05 0.0E+00 8.2E+05 0.0E+00 26S proteasome non-ATPase regulatory 653 P26516 PSMD7 1 5.3 36.5 321 2 1.8E+06 1.9E+06 2.5E+06 1.9E+06 2.4E+06 4.7E+06 subunit 7 654 Q9D710 Thioredoxin-related transmembrane protein 2 TMX2 3 12.2 33.9 295 12 1.8E+06 2.3E+06 3.2E+06 5.4E+06 1.0E+07 1.3E+07

655 Q9DCA5 Ribosome biogenesis protein BRX1 homolog BRIX1 3 9.9 41.2 353 17 1.8E+06 2.6E+06 3.4E+06 2.8E+06 1.8E+06 1.5E+06 656 Q8BK72 28S ribosomal protein S27, mitochondrial MRPS27 3 9.2 47.8 415 18 1.7E+06 1.2E+06 1.3E+06 3.7E+06 1.8E+06 0.0E+00 657 P47738 Aldehyde dehydrogenase, mitochondrial ALDH2 4 9.6 56.5 519 20 1.7E+06 0.0E+00 5.0E+06 2.6E+06 2.3E+06 2.4E+06 658 Q8BSY0 Aspartyl/asparaginyl beta-hydroxylase ASPH 4 7.4 83.0 741 9 1.7E+06 0.0E+00 2.6E+06 3.6E+06 2.4E+06 2.3E+06 659 Q921H8 3-ketoacyl-CoA thiolase A, peroxisomal ACAA1A 3 12.3 44.0 424 11 1.7E+06 1.7E+06 1.9E+06 2.2E+06 2.7E+06 2.1E+06 660 Q8VH51 RNA-binding protein 39 RBM39 2 4.9 59.4 530 4 1.6E+06 2.0E+06 0.0E+00 1.3E+06 2.4E+06 1.8E+06 661 Q9D125 28S ribosomal protein S25, mitochondrial MRPS25 1 7.0 19.9 171 3 1.6E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 662 Q8VCM8 Nicalin NCLN 3 6.9 62.9 563 9 1.5E+06 3.4E+06 1.7E+06 2.8E+06 2.3E+06 2.1E+06 663 Q9QUR6 Prolyl endopeptidase PREP 2 3.8 80.8 710 4 1.5E+06 0.0E+00 1.4E+06 1.6E+06 1.9E+06 3.2E+06 Supplementary file 4A : (continued) 664 P17426 AP-2 complex subunit alpha-1 AP2A1 2 5.2 107.7 977 4 1.5E+06 0.0E+00 1.2E+06 0.0E+00 0.0E+00 0.0E+00 665 P47802 Metaxin-1 MTX1 1 4.4 35.6 317 4 1.4E+06 3.9E+06 1.6E+06 2.8E+06 3.9E+06 5.2E+06 666 Q3UYV9 Nuclear cap-binding protein subunit 1 NCBP1 5 7.6 91.9 790 10 1.4E+06 2.2E+06 1.3E+06 0.0E+00 9.7E+05 1.3E+06 667 Q9D5V6 Synapse-associated protein 1 SYAP1 1 4.1 41.3 365 3 1.4E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 668 Q8R180 ERO1-like protein alpha ERO1L 3 7.1 54.1 464 9 1.3E+06 1.2E+06 4.1E+06 1.8E+06 2.0E+06 2.6E+06 669 Q91V12 Cytosolic acyl coenzyme A thioester hydrolase ACOT7 2 5.8 42.5 381 5 1.3E+06 2.2E+06 7.7E+05 3.1E+06 3.2E+06 2.0E+06 670 Q8C5Q4 G-rich sequence factor 1 GRSF1 1 4.6 53.1 479 2 1.3E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 671 Q8VHX6 Filamin-C FLNC 4 2.6 291.1 2726 7 1.2E+06 2.0E+06 2.0E+06 7.8E+06 2.8E+06 3.2E+06 Sister chromatid cohesion protein PDS5 672 Q4VA53 PDS5B 2 1.5 164.4 1446 4 1.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 homolog B 673 Q61879 Myosin-10 MYH10 2 5.3 229.0 1976 3 1.1E+06 0.0E+00 0.0E+00 9.1E+05 0.0E+00 0.0E+00 674 P55786 Puromycin-sensitive aminopeptidase NPEPPS 2 2.4 103.3 919 5 1.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 675 Q0GNC1 Inverted formin-2 INF2 2 1.5 138.6 1273 6 1.0E+06 0.0E+00 7.7E+05 1.6E+06 0.0E+00 1.5E+06 676 Q9QX47 Protein SON SON 2 1.1 265.7 2444 9 1.0E+06 1.3E+06 0.0E+00 7.8E+05 0.0E+00 0.0E+00 Eukaryotic translation initiation factor 3 subunit 677 P60229 EIF3E 2 4.9 52.2 445 3 7.2E+05 1.0E+06 0.0E+00 1.2E+06 1.0E+06 1.2E+06 E 678 P26369 Splicing factor U2AF 65 kDa subunit U2AF2 4 7.2 53.5 475 8 5.0E+05 0.0E+00 0.0E+00 1.8E+06 0.0E+00 0.0E+00 679 Q7Z5P9 Mucin-19 MUC19 1 0.2 805.2 8384 2 0.0E+00 8.7E+08 8.9E+08 6.8E+08 6.0E+08 6.7E+08 Zinc finger protein with KRAB and SCAN 680 Q9Y2L8 ZKSCAN5 1 2.1 96.9 839 2 0.0E+00 1.1E+08 0.0E+00 0.0E+00 0.0E+00 0.0E+00 domains 5 681 P20929 Nebulin NEB 2 0.3 772.9 6669 3 0.0E+00 9.1E+07 4.6E+07 0.0E+00 0.0E+00 0.0E+00 682 P68433 Histone H3.1 HIST1H3A 1 46.3 15.4 136 24 0.0E+00 6.3E+07 9.1E+07 0.0E+00 1.9E+07 5.1E+07 683 O09131 Glutathione S-transferase omega-1 GSTO1 3 13.8 27.5 240 5 0.0E+00 4.9E+07 0.0E+00 0.0E+00 0.0E+00 0.0E+00 684 P63158 High mobility group protein B1 HMGB1 3 19.5 24.9 215 19 0.0E+00 3.5E+07 4.8E+07 0.0E+00 0.0E+00 0.0E+00 685 Q8BH95 Enoyl-CoA hydratase, mitochondrial ECHS1 4 19.0 31.5 290 26 0.0E+00 1.8E+07 2.9E+07 2.2E+07 1.5E+07 0.0E+00 Cytochrome c oxidase subunit 5B, 686 P19536 COX5B 3 31.2 13.8 128 12 0.0E+00 1.4E+07 1.7E+07 0.0E+00 1.1E+07 1.3E+07 mitochondrial Signal peptidase complex catalytic subunit 687 Q9R0P6 SEC11A 2 9.5 20.6 179 3 0.0E+00 1.1E+07 0.0E+00 0.0E+00 0.0E+00 0.0E+00 SEC11A 688 P56379 6.8 kDa mitochondrial proteolipid MP68 2 29.3 6.7 58 3 0.0E+00 9.2E+06 9.4E+06 1.1E+07 1.3E+07 1.4E+07 Hydroxyacyl-coenzyme A dehydrogenase, 689 Q61425 HADH 5 26.1 34.5 314 24 0.0E+00 9.0E+06 0.0E+00 2.7E+07 3.3E+07 2.8E+07 mitochondrial 690 Q9Y2Q5 Ragulator complex protein LAMTOR2 LAMTOR2 2 26.4 13.5 125 13 0.0E+00 8.8E+06 4.8E+06 0.0E+00 0.0E+00 1.1E+07 691 P46779 60S ribosomal protein L28 RPL28 1 7.3 15.7 137 6 0.0E+00 8.2E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 692 O08734 Bcl-2 homologous antagonist/killer BAK1 2 17.2 23.3 209 9 0.0E+00 7.9E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 693 Q13185 Chromobox protein homolog 3 CBX3 2 14.2 20.8 183 56 0.0E+00 7.9E+06 9.6E+06 3.9E+06 5.3E+06 4.6E+06 694 Q9Z2U0 Proteasome subunit alpha type-7 PSMA7 2 10.5 27.9 248 4 0.0E+00 7.3E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 Succinate dehydrogenase [ubiquinone] 695 Q9CXV1 SDHD 2 22.6 17.0 159 9 0.0E+00 6.8E+06 0.0E+00 0.0E+00 1.4E+07 1.2E+07 cytochrome b small subunit, mitochondrial 696 Q8R404 Protein QIL1 QIL1 3 41.2 13.4 119 4 0.0E+00 6.5E+06 5.8E+06 0.0E+00 0.0E+00 5.6E+06 Plasma membrane calcium-transporting 697 G5E829 ATP2B1 6 6.3 134.8 1220 29 0.0E+00 6.4E+06 5.6E+06 7.0E+06 6.6E+06 8.0E+06 ATPase 1 Structural maintenance of chromosomes 698 Q6P5D8 SMCHD1 2 1.0 225.7 2007 3 0.0E+00 5.8E+06 0.0E+00 1.5E+06 0.0E+00 2.6E+06 flexible hinge domain-containing protein 1 699 P52293 Importin subunit alpha-1 KPNA2 4 13.8 57.9 529 9 0.0E+00 5.4E+06 2.1E+06 3.0E+06 4.5E+06 3.5E+06 700 Q6DRA6 Putative histone H2B type 2-D HIST2H2BD 1 17.7 18.0 164 3 0.0E+00 5.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 701 Q15365 Poly(rC)-binding protein 1 PCBP1 2 9.8 37.5 356 11 0.0E+00 4.9E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 702 Q922D8 C-1-tetrahydrofolate synthase, cytoplasmic MTHFD1 4 5.6 101.2 935 7 0.0E+00 4.7E+06 4.7E+06 8.4E+06 5.8E+06 5.0E+06 703 Q80WJ7 Protein LYRIC MTDH 2 4.0 63.8 579 8 0.0E+00 4.6E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 704 Q9CPU4 Microsomal glutathione S-transferase 3 MGST3 2 24.8 17.0 153 21 0.0E+00 4.5E+06 0.0E+00 0.0E+00 3.9E+07 3.4E+07 705 Q9CXY6 Interleukin enhancer-binding factor 2 ILF2 2 6.2 43.1 390 7 0.0E+00 4.5E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 706 Q7Z406 Myosin-14 MYH14 1 2.9 227.9 1995 3 0.0E+00 4.5E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 707 Q569Z6 Thyroid hormone receptor-associated protein 3 THRAP3 2 2.8 108.2 951 3 0.0E+00 4.4E+06 0.0E+00 2.6E+06 0.0E+00 0.0E+00 708 Q9ESX5 H/ACA ribonucleoprotein complex subunit 4 DKC1 2 6.7 57.4 509 5 0.0E+00 4.4E+06 2.7E+06 0.0E+00 0.0E+00 0.0E+00 709 P62774 Myotrophin MTPN 2 32.2 12.9 118 9 0.0E+00 4.3E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 710 Q9Z1Q5 Chloride intracellular channel protein 1 CLIC1 1 7.5 27.0 241 8 0.0E+00 4.3E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 711 Q8K363 ATP-dependent RNA helicase DDX18 DDX18 8 14.5 74.2 660 14 0.0E+00 4.2E+06 3.2E+06 6.1E+06 6.2E+06 5.2E+06 Single-stranded DNA-binding protein, 712 Q04837 SSBP1 2 22.3 17.3 148 84 0.0E+00 4.2E+06 4.1E+06 0.0E+00 0.0E+00 0.0E+00 mitochondrial Catechol O-methyltransferase domain- 713 Q8BIG7 COMTD1 4 21.8 29.0 262 7 0.0E+00 4.2E+06 5.1E+06 1.1E+07 1.7E+07 9.8E+06 containing protein 1 714 Q9EQU5 Protein SET SET 2 15.9 33.4 289 6 0.0E+00 4.2E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 715 O70252 Heme oxygenase 2 HMOX2 3 16.2 35.7 315 36 0.0E+00 4.1E+06 3.5E+06 6.3E+06 1.4E+07 1.3E+07 716 Q8BVY0 Ribosomal L1 domain-containing protein 1 RSL1D1 2 7.7 50.4 452 12 0.0E+00 4.1E+06 1.8E+06 2.3E+06 2.8E+06 2.2E+06 717 P62843 40S ribosomal protein S15 RPS15 2 31.7 17.0 145 11 0.0E+00 4.0E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 718 Q3U1J4 DNA damage-binding protein 1 DDB1 5 7.2 126.9 1140 12 0.0E+00 3.9E+06 3.9E+06 4.0E+06 3.9E+06 3.7E+06 719 O70318 Band 4.1-like protein 2 EPB41L2 2 3.3 109.9 988 2 0.0E+00 3.8E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 720 P97493 Thioredoxin, mitochondrial TXN2 2 24.1 18.3 166 4 0.0E+00 3.7E+06 6.6E+06 8.3E+06 9.3E+06 8.2E+06 721 Q9Z2U1 Proteasome subunit alpha type-5 PSMA5 2 10.8 26.4 241 12 0.0E+00 3.6E+06 1.6E+06 3.7E+06 3.6E+06 5.9E+06 722 P0DN76 Splicing factor U2AF 35 kDa subunit U2AF1 4 16.7 27.9 240 9 0.0E+00 3.6E+06 4.5E+06 0.0E+00 3.7E+06 2.9E+06 723 O88587 Catechol O-methyltransferase COMT 2 14.3 29.5 265 2 0.0E+00 3.5E+06 2.7E+06 4.0E+06 4.3E+06 6.7E+06 724 P61226 Ras-related protein Rap-2b RAP2B 2 14.8 20.5 183 10 0.0E+00 3.3E+06 3.2E+06 4.0E+06 3.4E+06 3.8E+06 725 P49722 Proteasome subunit alpha type-2 PSMA2 2 14.1 25.9 234 16 0.0E+00 3.2E+06 2.7E+06 4.5E+06 3.8E+06 8.2E+06 726 B2RXS4 Plexin-B2 PLXNB2 3 3.7 206.2 1842 5 0.0E+00 3.1E+06 0.0E+00 0.0E+00 0.0E+00 1.8E+06 727 Q4KML4 Costars family protein ABRACL ABRACL 2 35.8 9.0 81 7 0.0E+00 3.0E+06 3.4E+06 6.7E+06 3.9E+06 6.4E+06 Polypeptide N-acetylgalactosaminyltransferase 728 Q6PB93 GALNT2 2 4.7 64.5 570 3 0.0E+00 3.0E+06 3.2E+06 0.0E+00 0.0E+00 0.0E+00 2 729 Q9JIW9 Ras-related protein Ral-B RALB 2 10.2 23.3 206 8 0.0E+00 3.0E+06 2.7E+06 0.0E+00 0.0E+00 0.0E+00 Serine/threonine-protein phosphatase 2A 65 730 Q76MZ3 PPP2R1A 4 10.7 65.3 589 7 0.0E+00 2.9E+06 2.4E+06 2.5E+06 3.9E+06 2.7E+06 kDa regulatory subunit A alpha isoform 731 Q13322 Growth factor receptor-bound protein 10 GRB10 2 4.5 67.2 594 11 0.0E+00 2.9E+06 2.3E+06 0.0E+00 0.0E+00 0.0E+00 732 P70698 CTP synthase 1 CTPS1 2 5.8 66.7 591 15 0.0E+00 2.8E+06 4.4E+06 0.0E+00 1.4E+06 1.0E+06 733 Q60864 Stress-induced-phosphoprotein 1 STIP1 3 6.8 62.6 543 29 0.0E+00 2.7E+06 4.8E+06 5.0E+06 3.1E+06 0.0E+00 734 Q15019 Septin-2 Sep-02 2 7.8 41.5 361 12 0.0E+00 2.6E+06 2.2E+06 2.8E+06 0.0E+00 2.7E+06 735 P40124 Adenylyl cyclase-associated protein 1 CAP1 2 8.6 51.6 474 14 0.0E+00 2.6E+06 0.0E+00 0.0E+00 1.5E+06 1.6E+06 Guanine nucleotide-binding protein subunit 736 P29992 GNA11 2 10.6 42.1 359 10 0.0E+00 2.6E+06 0.0E+00 3.2E+06 3.0E+06 0.0E+00 alpha-11 GTP:AMP phosphotransferase AK3, 737 Q9WTP7 AK3 2 11.5 25.4 227 5 0.0E+00 2.5E+06 2.7E+06 3.7E+06 3.7E+06 6.8E+06 mitochondrial 738 P55096 ATP-binding cassette sub-family D member 3 ABCD3 1 1.8 75.5 659 4 0.0E+00 2.5E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 739 Q921M3 Splicing factor 3B subunit 3 SF3B3 2 2.1 135.6 1217 5 0.0E+00 2.2E+06 4.8E+06 1.8E+06 0.0E+00 1.9E+06 740 Q9D0R2 Threonine--tRNA ligase, cytoplasmic TARS 2 2.9 83.4 722 17 0.0E+00 2.2E+06 2.1E+06 0.0E+00 0.0E+00 0.0E+00 741 Q9Z2G6 Protein sel-1 homolog 1 SEL1L 2 3.8 88.3 790 5 0.0E+00 2.2E+06 1.3E+06 0.0E+00 0.0E+00 1.3E+06 742 P06745 Glucose-6-phosphate isomerase GPI 3 7.5 62.8 558 8 0.0E+00 2.1E+06 2.6E+06 5.0E+06 0.0E+00 0.0E+00 743 Q14978 Nucleolar and coiled-body phosphoprotein 1 NOLC1 1 3.3 73.6 699 22 0.0E+00 2.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 744 Q99K70 Ras-related GTP-binding protein C RRAGC 2 4.5 44.1 398 4 0.0E+00 2.0E+06 9.7E+05 9.4E+05 8.2E+05 7.7E+05 745 Q9Y265 RuvB-like 1 RUVBL1 3 9.0 50.2 456 5 0.0E+00 2.0E+06 2.4E+06 1.8E+06 1.9E+06 0.0E+00 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Alkyldihydroxyacetonephosphate synthase, 746 Q8C0I1 AGPS 2 5.3 71.7 645 6 0.0E+00 2.0E+06 0.0E+00 3.3E+06 2.7E+06 2.6E+06 peroxisomal 747 P40142 Transketolase TKT 2 4.2 67.6 623 8 0.0E+00 2.0E+06 0.0E+00 2.5E+06 2.1E+06 2.5E+06 Vitamin K epoxide reductase complex subunit 1- 748 Q8N0U8 VKORC1L1 1 6.2 19.8 176 3 0.0E+00 2.0E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 like protein 1 749 Q80X90 Filamin-B FLNB 4 2.8 277.8 2602 6 0.0E+00 1.9E+06 2.9E+06 1.8E+06 0.0E+00 2.1E+06 Eukaryotic translation initiation factor 2 subunit 750 Q9Z0N2 EIF2S3Y 1 5.3 51.1 472 3 0.0E+00 1.9E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3, Y-linked 751 Q9Z277 Tyrosine-protein kinase BAZ1B BAZ1B 2 2.1 170.7 1479 6 0.0E+00 1.8E+06 0.0E+00 0.0E+00 6.1E+05 0.0E+00 Guanine nucleotide-binding protein G(k) subunit 752 Q9DC51 GNAI3 1 21.5 40.5 354 38 0.0E+00 1.7E+06 1.8E+06 1.5E+06 1.1E+06 1.1E+06 alpha 753 Q9CVB6 Actin-related protein 2/3 complex subunit 2 ARPC2 2 16.0 34.4 300 14 0.0E+00 1.7E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 754 P13595 Neural cell adhesion molecule 1 NCAM1 2 2.2 119.4 1115 5 0.0E+00 1.7E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 755 Q9Z1Q9 Valine--tRNA ligase VARS 2 2.1 140.2 1263 3 0.0E+00 1.7E+06 0.0E+00 2.1E+06 0.0E+00 0.0E+00 756 P62911 60S ribosomal protein L32 RPL32 1 7.4 15.9 135 2 0.0E+00 1.6E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 757 Q9NX47 E3 ubiquitin-protein ligase MARCH5 Mar-05 2 10.8 31.2 278 5 0.0E+00 1.6E+06 1.8E+06 0.0E+00 3.5E+06 2.4E+06 758 P43135 COUP transcription factor 2 NR2F2 2 7.7 45.6 414 4 0.0E+00 1.6E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 759 Q8C4J7 Transducin beta-like protein 3 TBL3 2 3.0 88.3 801 12 0.0E+00 1.6E+06 1.4E+06 1.1E+06 0.0E+00 0.0E+00 760 Q8JZR0 Long-chain-fatty-acid--CoA ligase 5 ACSL5 2 4.4 76.2 683 7 0.0E+00 1.5E+06 9.9E+05 1.1E+06 1.9E+06 0.0E+00 6-phosphogluconate dehydrogenase, 761 Q9DCD0 PGD 2 7.0 53.2 483 42 0.0E+00 1.5E+06 0.0E+00 3.1E+06 4.7E+06 2.9E+06 decarboxylating 762 Q8NHH9 Atlastin-2 ATL2 2 4.1 66.2 583 2 0.0E+00 1.3E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 763 Q9UBF2 Coatomer subunit gamma-2 COPG2 2 3.3 97.6 871 4 0.0E+00 1.3E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 764 Q9NTK5 Obg-like ATPase 1 OLA1 1 3.8 44.7 396 3 0.0E+00 1.2E+06 1.2E+06 0.0E+00 1.5E+06 0.0E+00 765 Q9Y2P8 RNA 3-terminal phosphate cyclase-like protein RCL1 1 4.0 40.8 373 2 0.0E+00 1.1E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 766 Q5SSJ5 Heterochromatin protein 1-binding protein 3 HP1BP3 2 4.7 61.2 553 4 0.0E+00 1.1E+06 8.8E+05 1.8E+06 3.3E+06 3.0E+06 767 Q9Z2N8 Actin-like protein 6A ACTL6A 1 3.0 47.4 429 2 0.0E+00 1.0E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 768 Q9UKA9 Polypyrimidine tract-binding protein 2 PTBP2 1 5.6 57.5 531 5 0.0E+00 1.0E+06 0.0E+00 0.0E+00 0.0E+00 0.0E+00 769 Q8BU03 Periodic tryptophan protein 2 homolog PWP2 2 2.6 102.9 919 3 0.0E+00 9.9E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 Double-strand-break repair protein rad21 770 O60216 RAD21 2 3.3 71.7 631 2 0.0E+00 9.8E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 homolog Very long-chain specific acyl-CoA 771 P50544 ACADVL 1 2.9 70.9 656 13 0.0E+00 9.5E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 dehydrogenase, mitochondrial 772 Q99LR1 Monoacylglycerol lipase ABHD12 ABHD12 2 6.8 45.3 398 4 0.0E+00 9.5E+05 0.0E+00 0.0E+00 0.0E+00 2.3E+06 773 Q99K51 Plastin-3 PLS3 2 4.1 70.7 630 13 0.0E+00 9.3E+05 0.0E+00 0.0E+00 1.7E+06 8.0E+05 774 Q8N3U4 Cohesin subunit SA-2 STAG2 2 2.1 141.3 1231 4 0.0E+00 7.7E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 Supplementary file 4A : (continued) 775 Q9Y490 Talin-1 TLN1 3 1.7 269.8 2541 5 0.0E+00 7.5E+05 1.2E+06 0.0E+00 0.0E+00 0.0E+00 776 Q9DC50 Peroxisomal carnitine O-octanoyltransferase CROT 2 4.4 70.3 612 3 0.0E+00 7.1E+05 0.0E+00 1.1E+06 1.1E+06 1.6E+06 777 P70699 Lysosomal alpha-glucosidase GAA 2 3.3 106.3 953 2 0.0E+00 6.8E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 778 Q9R0Y5 Adenylate kinase isoenzyme 1 AK1 1 11.9 21.5 194 2 0.0E+00 6.6E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 779 Q920A7 AFG3-like protein 1 AFG3L1 1 1.8 87.0 789 3 0.0E+00 5.8E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 780 Q62086 Serum paraoxonase/arylesterase 2 PON2 2 9.6 39.6 354 6 0.0E+00 5.7E+05 1.7E+06 1.7E+06 2.2E+06 1.6E+06 781 Q9H583 HEAT repeat-containing protein 1 HEATR1 2 1.1 242.4 2144 8 0.0E+00 5.5E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 782 P28658 Ataxin-10 ATXN10 2 5.7 53.7 475 5 0.0E+00 5.4E+05 4.7E+05 0.0E+00 0.0E+00 5.7E+05 783 Q14677 Clathrin interactor 1 CLINT1 1 1.6 68.3 625 4 0.0E+00 3.9E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 784 Q9CR16 Peptidyl-prolyl cis-trans isomerase D PPID 2 6.2 40.7 370 5 0.0E+00 3.6E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 cAMP-dependent protein kinase type I-alpha 785 Q9DBC7 PRKAR1A 1 6.3 43.2 381 3 0.0E+00 3.5E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 regulatory subunit 786 Q9QYJ0 DnaJ homolog subfamily A member 2 DNAJA2 1 3.6 45.7 412 3 0.0E+00 3.2E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 787 Q61735 Leukocyte surface antigen CD47 CD47 1 4.6 33.1 303 2 0.0E+00 2.8E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 788 G5E861 Sodium channel and clathrin linker 1 SCLT1 1 2.2 80.5 688 2 0.0E+00 2.5E+05 0.0E+00 0.0E+00 0.0E+00 0.0E+00 789 Q8CE64 Zinc finger protein 276 ZNF276 1 3.3 67.3 614 2 0.0E+00 0.0E+00 9.5E+07 0.0E+00 0.0E+00 0.0E+00 790 P10412 Histone H1.4 HIST1H1E 1 36.1 21.9 219 5 0.0E+00 0.0E+00 2.0E+07 0.0E+00 0.0E+00 0.0E+00 Succinyl-CoA ligase [ADP/GDP-forming] subunit 791 Q9WUM5 SUCLG1 2 7.8 36.2 346 5 0.0E+00 0.0E+00 1.3E+07 0.0E+00 0.0E+00 0.0E+00 alpha, mitochondrial 792 Q9CQN6 Transmembrane protein 14C TMEM14C 2 35.1 11.6 114 9 0.0E+00 0.0E+00 9.2E+06 0.0E+00 1.1E+07 1.2E+07 Large neutral amino acids transporter small 793 Q9Z127 SLC7A5 1 2.7 55.9 512 3 0.0E+00 0.0E+00 8.7E+06 0.0E+00 0.0E+00 0.0E+00 subunit 1 Transmembrane emp24 domain-containing 794 Q8R1V4 TMED4 2 12.8 26.0 227 2 0.0E+00 0.0E+00 8.5E+06 0.0E+00 9.0E+06 8.0E+06 protein 4 795 Q9H0U4 Ras-related protein Rab-1B RAB1B 1 31.8 22.2 201 3 0.0E+00 0.0E+00 7.7E+06 8.4E+06 0.0E+00 0.0E+00 796 Q8BWT1 3-ketoacyl-CoA thiolase, mitochondrial ACAA2 3 10.6 41.8 397 12 0.0E+00 0.0E+00 6.5E+06 8.4E+06 9.1E+06 8.3E+06 797 P58044 Isopentenyl-diphosphate Delta-isomerase 1 IDI1 2 9.3 26.3 227 32 0.0E+00 0.0E+00 6.3E+06 0.0E+00 3.7E+06 6.4E+06 Transmembrane and coiled-coil domain- 798 Q9UM00 TMCO1 1 8.0 21.2 188 14 0.0E+00 0.0E+00 5.8E+06 1.1E+07 1.3E+07 1.9E+07 containing protein 1 799 Q9P0I2 ER membrane protein complex subunit 3 EMC3 2 9.6 30.0 261 8 0.0E+00 0.0E+00 5.5E+06 0.0E+00 0.0E+00 0.0E+00 800 Q9NYL4 Peptidyl-prolyl cis-trans isomerase FKBP11 FKBP11 1 5.0 22.2 201 2 0.0E+00 0.0E+00 5.0E+06 0.0E+00 0.0E+00 0.0E+00 801 P18242 Cathepsin D CTSD 2 4.6 45.0 410 5 0.0E+00 0.0E+00 4.9E+06 0.0E+00 0.0E+00 0.0E+00 802 Q8IYT4 Katanin p60 ATPase-containing subunit A-like 2 KATNAL2 1 2.2 61.3 538 2 0.0E+00 0.0E+00 4.7E+06 0.0E+00 0.0E+00 0.0E+00 803 Q9DBP5 UMP-CMP kinase CMPK1 3 15.8 22.2 196 3 0.0E+00 0.0E+00 4.6E+06 6.5E+06 4.6E+06 4.3E+06 804 P02469 Laminin subunit beta-1 LAMB1 5 3.5 197.1 1786 16 0.0E+00 0.0E+00 4.3E+06 5.6E+06 4.8E+06 5.0E+06 805 Q9D1K2 V-type proton ATPase subunit F ATP6V1F 1 20.2 13.4 119 4 0.0E+00 0.0E+00 4.3E+06 0.0E+00 2.4E+06 3.1E+06 806 Q91V92 ATP-citrate synthase ACLY 5 6.2 119.7 1091 12 0.0E+00 0.0E+00 3.6E+06 3.7E+06 3.3E+06 4.6E+06 NADH dehydrogenase [ubiquinone] 1 beta 807 Q3UIU2 NDUFB6 2 13.3 15.5 128 2 0.0E+00 0.0E+00 3.4E+06 0.0E+00 0.0E+00 8.3E+06 subcomplex subunit 6 808 P21810 Biglycan BGN 1 3.0 41.7 368 3 0.0E+00 0.0E+00 3.2E+06 0.0E+00 0.0E+00 0.0E+00 Sodium-coupled neutral amino acid transporter 809 Q8R1S9 SLC38A4 1 1.8 60.5 547 8 0.0E+00 0.0E+00 3.1E+06 0.0E+00 0.0E+00 0.0E+00 4 810 O88668 Protein CREG1 CREG1 2 13.2 24.5 220 3 0.0E+00 0.0E+00 2.7E+06 3.3E+06 3.0E+06 0.0E+00 NADH dehydrogenase [ubiquinone] 1 alpha 811 Q9CPP6 NDUFA5 1 17.2 13.4 116 2 0.0E+00 0.0E+00 2.6E+06 0.0E+00 0.0E+00 0.0E+00 subcomplex subunit 5 812 Q8N1F7 Nuclear pore complex protein Nup93 NUP93 2 4.4 93.5 819 4 0.0E+00 0.0E+00 2.6E+06 0.0E+00 0.0E+00 2.4E+06 Acyl-CoA synthetase family member 2, 813 Q8VCW8 ACSF2 4 10.2 68.0 615 14 0.0E+00 0.0E+00 2.6E+06 6.3E+06 5.6E+06 5.1E+06 mitochondrial 814 Q9CWJ9 Bifunctional purine biosynthesis protein PURH ATIC 4 9.8 64.2 592 7 0.0E+00 0.0E+00 2.5E+06 5.1E+06 0.0E+00 0.0E+00 815 Q8BM55 Transmembrane protein 214 TMEM214 1 2.0 76.4 687 3 0.0E+00 0.0E+00 2.3E+06 0.0E+00 0.0E+00 0.0E+00 816 Q99JF8 PC4 and SFRS1-interacting protein PSIP1 2 5.3 59.7 528 4 0.0E+00 0.0E+00 2.1E+06 0.0E+00 0.0E+00 0.0E+00 817 Q8IXI2 Mitochondrial Rho GTPase 1 RHOT1 3 6.8 70.8 618 14 0.0E+00 0.0E+00 2.0E+06 2.1E+06 0.0E+00 1.5E+06 818 O95573 Long-chain-fatty-acid--CoA ligase 3 ACSL3 2 3.9 80.4 720 4 0.0E+00 0.0E+00 1.9E+06 1.7E+06 0.0E+00 2.6E+06 NADH dehydrogenase [ubiquinone] iron-sulfur 819 Q8K3J1 NDUFS8 2 9.4 24.0 212 3 0.0E+00 0.0E+00 1.9E+06 1.5E+06 1.1E+06 0.0E+00 protein 8, mitochondrial 820 Q8VDF2 E3 ubiquitin-protein ligase UHRF1 UHRF1 2 3.8 88.3 782 9 0.0E+00 0.0E+00 1.7E+06 0.0E+00 0.0E+00 0.0E+00 Alpha-2-macroglobulin receptor-associated 821 P55302 LRPAP1 1 3.6 42.2 360 2 0.0E+00 0.0E+00 9.6E+05 0.0E+00 0.0E+00 0.0E+00 protein 822 Q9JII5 DAZ-associated protein 1 DAZAP1 1 3.9 43.2 406 9 0.0E+00 0.0E+00 8.9E+05 0.0E+00 0.0E+00 0.0E+00 823 Q9ER41 Torsin-1B TOR1B 3 14.6 37.8 336 6 0.0E+00 0.0E+00 8.7E+05 5.1E+05 1.8E+06 0.0E+00 26S proteasome non-ATPase regulatory 824 Q8VDM4 PSMD2 2 3.1 100.2 908 2 0.0E+00 0.0E+00 8.2E+05 1.4E+06 2.7E+06 1.2E+06 subunit 2 825 Q13112 Chromatin assembly factor 1 subunit B CHAF1B 1 2.0 61.5 559 2 0.0E+00 0.0E+00 7.9E+05 0.0E+00 0.0E+00 0.0E+00 826 P50516 V-type proton ATPase catalytic subunit A ATP6V1A 1 2.9 68.3 617 8 0.0E+00 0.0E+00 7.5E+05 0.0E+00 0.0E+00 0.0E+00 827 Q02819 Nucleobindin-1 NUCB1 2 6.3 53.4 459 2 0.0E+00 0.0E+00 7.2E+05 0.0E+00 0.0E+00 0.0E+00 828 Q14690 Protein RRP5 homolog PDCD11 2 2.7 208.7 1871 2 0.0E+00 0.0E+00 6.2E+05 0.0E+00 0.0E+00 0.0E+00 829 P70333 Heterogeneous nuclear ribonucleoprotein H2 HNRNPH2 1 13.4 49.3 449 2 0.0E+00 0.0E+00 5.1E+05 0.0E+00 0.0E+00 0.0E+00 830 Q9BW92 Threonine--tRNA ligase, mitochondrial TARS2 1 1.4 81.0 718 4 0.0E+00 0.0E+00 4.9E+05 0.0E+00 0.0E+00 0.0E+00 831 Q15113 Procollagen C-endopeptidase enhancer 1 PCOLCE 1 2.0 48.0 449 2 0.0E+00 0.0E+00 4.4E+05 0.0E+00 0.0E+00 0.0E+00 832 P58107 Epiplakin EPPK1 1 3.6 555.7 5088 -2 0.0E+00 0.0E+00 3.2E+05 0.0E+00 0.0E+00 0.0E+00 Developmentally-regulated GTP-binding protein 833 Q9QXB9 DRG2 1 5.5 40.7 364 3 0.0E+00 0.0E+00 2.4E+05 0.0E+00 0.0E+00 0.0E+00 2 Mitochondrial import inner membrane 834 Q9WVA2 TIMM8A1 1 11.3 11.0 97 7 0.0E+00 0.0E+00 0.0E+00 6.7E+07 0.0E+00 0.0E+00 translocase subunit Tim8 A Lysosomal-associated transmembrane protein 835 Q60961 LAPTM4A 2 10.7 26.9 233 3 0.0E+00 0.0E+00 0.0E+00 3.1E+07 0.0E+00 1.9E+07 4A 836 P15532 Nucleoside diphosphate kinase A NME1 2 47.4 17.2 152 36 0.0E+00 0.0E+00 0.0E+00 2.7E+07 2.2E+07 2.2E+07 837 Q9CQW9 Interferon-induced transmembrane protein 3 IFITM3 2 26.3 15.0 137 21 0.0E+00 0.0E+00 0.0E+00 1.8E+07 9.2E+06 8.2E+06 838 P63323 40S ribosomal protein S12 RPS12 3 31.1 14.5 132 8 0.0E+00 0.0E+00 0.0E+00 1.8E+07 9.6E+06 8.9E+06 839 Q9CR21 Acyl carrier protein, mitochondrial NDUFAB1 2 14.7 17.4 156 3 0.0E+00 0.0E+00 0.0E+00 1.2E+07 7.1E+06 7.2E+06 840 P61514 60S ribosomal protein L37a RPL37A 1 19.6 10.3 92 49 0.0E+00 0.0E+00 0.0E+00 1.2E+07 0.0E+00 0.0E+00 Dual 3,5-cyclic-AMP and -GMP 841 Q9HCR9 PDE11A 1 1.1 104.8 933 -2 0.0E+00 0.0E+00 0.0E+00 1.1E+07 0.0E+00 0.0E+00 phosphodiesterase 11A Vesicle-associated membrane protein- 842 Q9QY76 VAPB 1 10.7 26.9 243 2 0.0E+00 0.0E+00 0.0E+00 9.2E+06 0.0E+00 0.0E+00 associated protein B Oligosaccharyltransferase complex subunit 843 Q9NRP0 OSTC 1 8.1 16.8 149 11 0.0E+00 0.0E+00 0.0E+00 8.3E+06 0.0E+00 0.0E+00 OSTC 844 P97461 40S ribosomal protein S5 RPS5 1 28.9 22.9 204 2 0.0E+00 0.0E+00 0.0E+00 8.0E+06 0.0E+00 0.0E+00 845 Q9UNL2 Translocon-associated protein subunit gamma SSR3 1 7.6 21.1 185 10 0.0E+00 0.0E+00 0.0E+00 5.6E+06 0.0E+00 0.0E+00 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

846 P31001 Desmin DES 2 9.4 53.5 469 2 0.0E+00 0.0E+00 0.0E+00 5.5E+06 0.0E+00 0.0E+00 Long-chain specific acyl-CoA dehydrogenase, 847 P28330 ACADL 2 4.2 47.7 430 4 0.0E+00 0.0E+00 0.0E+00 5.2E+06 0.0E+00 4.1E+06 mitochondrial 848 P51660 Peroxisomal multifunctional enzyme type 2 HSD17B4 2 3.7 79.5 735 7 0.0E+00 0.0E+00 0.0E+00 5.0E+06 3.4E+06 3.9E+06 Recombining binding protein suppressor of 849 Q06330 RBPJ 2 4.4 55.6 500 3 0.0E+00 0.0E+00 0.0E+00 5.0E+06 0.0E+00 0.0E+00 hairless 850 O43852 Calumenin CALU 1 7.6 37.1 315 3 0.0E+00 0.0E+00 0.0E+00 4.2E+06 0.0E+00 0.0E+00 851 Q9UBX8 Beta-1,4-galactosyltransferase 6 B4GALT6 1 2.4 44.9 382 -2 0.0E+00 0.0E+00 0.0E+00 3.5E+06 0.0E+00 0.0E+00 852 Q9Y4Y9 U6 snRNA-associated Sm-like protein LSm5 LSM5 1 20.9 9.9 91 2 0.0E+00 0.0E+00 0.0E+00 3.4E+06 0.0E+00 0.0E+00 853 Q9D338 39S ribosomal protein L19, mitochondrial MRPL19 2 9.2 33.6 292 3 0.0E+00 0.0E+00 0.0E+00 3.4E+06 0.0E+00 0.0E+00 854 Q9JKF1 Ras GTPase-activating-like protein IQGAP1 IQGAP1 4 4.0 188.7 1657 8 0.0E+00 0.0E+00 0.0E+00 2.9E+06 3.1E+06 5.1E+06 855 Q9CYN9 Renin receptor ATP6AP2 2 10.9 39.1 350 6 0.0E+00 0.0E+00 0.0E+00 2.7E+06 0.0E+00 0.0E+00 856 Q8C854 Myelin expression factor 2 MYEF2 2 3.6 63.3 591 4 0.0E+00 0.0E+00 0.0E+00 2.7E+06 2.3E+06 0.0E+00 857 Q86VP6 Cullin-associated NEDD8-dissociated protein 1 CAND1 3 3.3 136.4 1230 6 0.0E+00 0.0E+00 0.0E+00 2.7E+06 3.0E+06 1.5E+06 858 P61021 Ras-related protein Rab-5B RAB5B 1 16.7 23.7 215 4 0.0E+00 0.0E+00 0.0E+00 2.6E+06 0.0E+00 0.0E+00 859 Q9R1Q9 V-type proton ATPase subunit S1 ATP6AP1 3 9.3 51.0 463 8 0.0E+00 0.0E+00 0.0E+00 2.5E+06 0.0E+00 7.7E+05 860 P05201 Aspartate aminotransferase, cytoplasmic GOT1 2 9.7 46.2 413 10 0.0E+00 0.0E+00 0.0E+00 2.4E+06 2.0E+06 0.0E+00 861 Q6PFR5 Transformer-2 protein homolog alpha TRA2A 2 8.2 32.3 281 12 0.0E+00 0.0E+00 0.0E+00 2.2E+06 0.0E+00 0.0E+00 Polyribonucleotide nucleotidyltransferase 1, 862 Q8TCS8 PNPT1 1 1.8 86.0 783 22 0.0E+00 0.0E+00 0.0E+00 2.1E+06 0.0E+00 0.0E+00 mitochondrial 863 P50518 V-type proton ATPase subunit E 1 ATP6V1E1 2 10.2 26.2 226 3 0.0E+00 0.0E+00 0.0E+00 1.9E+06 0.0E+00 0.0E+00 864 P46735 Unconventional myosin-Ib MYO1B 3 2.9 128.6 1107 7 0.0E+00 0.0E+00 0.0E+00 1.9E+06 1.7E+06 1.4E+06 865 Q8BXZ1 Protein disulfide-isomerase TMX3 TMX3 1 2.9 51.8 456 16 0.0E+00 0.0E+00 0.0E+00 1.8E+06 0.0E+00 0.0E+00 Heterogeneous nuclear ribonucleoprotein U-like 866 Q00PI9 HNRNPUL2 2 4.2 84.9 745 3 0.0E+00 0.0E+00 0.0E+00 1.7E+06 0.0E+00 0.0E+00 protein 2 867 Q9CXW3 Calcyclin-binding protein CACYBP 1 6.6 26.5 229 4 0.0E+00 0.0E+00 0.0E+00 1.6E+06 0.0E+00 0.0E+00 868 P48428 Tubulin-specific chaperone A TBCA 1 14.8 12.8 108 2 0.0E+00 0.0E+00 0.0E+00 1.5E+06 0.0E+00 0.0E+00 869 P47989 Xanthine dehydrogenase/oxidase XDH 1 0.9 146.4 1333 2 0.0E+00 0.0E+00 0.0E+00 1.5E+06 0.0E+00 0.0E+00 870 Q91ZE0 Trimethyllysine dioxygenase, mitochondrial TMLHE 2 5.7 49.6 421 4 0.0E+00 0.0E+00 0.0E+00 1.4E+06 0.0E+00 0.0E+00 871 Q9CQL4 39S ribosomal protein L20, mitochondrial MRPL20 2 14.1 17.6 149 4 0.0E+00 0.0E+00 0.0E+00 1.4E+06 0.0E+00 0.0E+00 872 Q8BU33 Acetolactate synthase-like protein ILVBL 2 6.5 68.2 632 3 0.0E+00 0.0E+00 0.0E+00 1.3E+06 0.0E+00 0.0E+00 873 P62334 26S protease regulatory subunit 10B PSMC6 1 3.6 44.2 389 4 0.0E+00 0.0E+00 0.0E+00 1.3E+06 0.0E+00 0.0E+00 Procollagen-lysine,2-oxoglutarate 5- 874 Q9R0B9 PLOD2 2 3.3 84.5 737 7 0.0E+00 0.0E+00 0.0E+00 1.2E+06 9.3E+05 0.0E+00 dioxygenase 2 Saccharopine dehydrogenase-like 875 Q8R127 SCCPDH 2 7.0 47.1 429 3 0.0E+00 0.0E+00 0.0E+00 1.2E+06 0.0E+00 0.0E+00 oxidoreductase 876 Q61263 Sterol O-acyltransferase 1 SOAT1 2 4.3 63.8 540 3 0.0E+00 0.0E+00 0.0E+00 1.1E+06 0.0E+00 0.0E+00 877 Q8C6U2 PQ-loop repeat-containing protein 3 PQLC3 1 4.5 22.7 202 2 0.0E+00 0.0E+00 0.0E+00 1.0E+06 0.0E+00 0.0E+00 878 P10605 Cathepsin B CTSB 1 5.3 37.3 339 2 0.0E+00 0.0E+00 0.0E+00 1.0E+06 0.0E+00 0.0E+00 Supplementary file 4A : (continued) 879 O35604 Niemann-Pick C1 protein NPC1 2 1.6 142.9 1277 3 0.0E+00 0.0E+00 0.0E+00 1.0E+06 2.9E+06 0.0E+00 26S proteasome non-ATPase regulatory 880 Q8BG32 PSMD11 2 5.9 47.4 422 2 0.0E+00 0.0E+00 0.0E+00 9.6E+05 0.0E+00 0.0E+00 subunit 11 881 Q8VHK9 ATP-dependent RNA helicase DHX36 DHX36 2 2.4 113.9 1001 3 0.0E+00 0.0E+00 0.0E+00 9.3E+05 0.0E+00 0.0E+00 882 Q9CWF2 Tubulin beta-2B chain TUBB2B 1 44.7 50.0 445 5 0.0E+00 0.0E+00 0.0E+00 7.1E+05 0.0E+00 0.0E+00 Replication protein A 70 kDa DNA-binding 883 P27694 RPA1 1 2.3 68.1 616 3 0.0E+00 0.0E+00 0.0E+00 6.9E+05 0.0E+00 0.0E+00 subunit 884 Q05769 Prostaglandin G/H synthase 2 PTGS2 2 4.8 69.0 604 3 0.0E+00 0.0E+00 0.0E+00 6.6E+05 0.0E+00 0.0E+00 885 Q99MN1 Lysine--tRNA ligase KARS 1 1.8 67.8 595 3 0.0E+00 0.0E+00 0.0E+00 6.5E+05 0.0E+00 0.0E+00 886 P12270 Nucleoprotein TPR TPR 1 0.8 267.3 2363 3 0.0E+00 0.0E+00 0.0E+00 5.8E+05 0.0E+00 0.0E+00 Tyrosine-protein phosphatase non-receptor type 887 P35821 PTPN1 1 2.5 49.6 432 3 0.0E+00 0.0E+00 0.0E+00 5.6E+05 0.0E+00 0.0E+00 1 888 P27708 CAD protein CAD 2 1.0 243.0 2225 2 0.0E+00 0.0E+00 0.0E+00 5.5E+05 0.0E+00 0.0E+00 2-oxoglutarate dehydrogenase-like, 889 Q9ULD0 OGDHL 1 6.6 114.5 1010 37 0.0E+00 0.0E+00 0.0E+00 5.3E+05 0.0E+00 0.0E+00 mitochondrial 890 Q91X78 Erlin-1 ERLIN1 1 11.8 38.9 346 2 0.0E+00 0.0E+00 0.0E+00 3.9E+05 0.0E+00 0.0E+00 891 P62814 V-type proton ATPase subunit B, brain isoform ATP6V1B2 1 4.1 56.6 511 4 0.0E+00 0.0E+00 0.0E+00 3.0E+05 0.0E+00 0.0E+00 892 P70295 Ancient ubiquitous protein 1 AUP1 1 4.4 46.1 410 2 0.0E+00 0.0E+00 0.0E+00 1.8E+05 0.0E+00 0.0E+00 ATP synthase F(0) complex subunit C1, 893 Q9CR84 ATP5G1 1 22.8 14.2 136 14 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.2E+07 2.5E+07 mitochondrial 894 P62748 Hippocalcin-like protein 1 HPCAL1 1 10.4 22.3 193 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.9E+07 0.0E+00 895 Q9CQE3 28S ribosomal protein S17, mitochondrial MRPS17 2 15.0 13.4 120 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.5E+06 0.0E+00 896 Q96JB3 Hypermethylated in cancer 2 protein HIC2 1 1.6 66.2 615 8 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.5E+06 0.0E+00 897 P52927 High mobility group protein HMGI-C HMGA2 1 8.3 11.8 108 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.4E+06 0.0E+00 898 P47757 F-actin-capping protein subunit beta CAPZB 1 3.6 31.3 277 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 7.3E+06 0.0E+00 899 Q60870 Receptor expression-enhancing protein 5 REEP5 1 5.4 21.1 185 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.7E+06 0.0E+00 900 Q9Y3E0 Vesicle transport protein GOT1B GOLT1B 1 10.1 15.4 138 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.4E+06 0.0E+00 Glycerol-3-phosphate dehydrogenase, 901 P43304 GPD2 1 17.2 80.9 727 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.1E+06 6.1E+06 mitochondrial 902 P63030 Mitochondrial pyruvate carrier 1 MPC1 2 26.6 12.5 109 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.8E+06 4.7E+06 903 Q8BGY7 Protein FAM210A FAM210A 2 12.8 31.6 273 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.3E+06 0.0E+00 904 P61211 ADP-ribosylation factor-like protein 1 ARL1 1 6.1 20.4 181 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.3E+06 0.0E+00 905 Q3TQ03 Circadian-associated transcriptional repressor CIART 1 3.5 40.4 375 -2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.8E+06 0.0E+00 906 Q8BJZ4 28S ribosomal protein S35, mitochondrial MRPS35 1 4.1 36.0 320 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.6E+06 0.0E+00 907 P50637 Translocator protein TSPO 2 30.2 18.8 169 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.5E+06 0.0E+00 Dolichol-phosphate mannosyltransferase 908 O70152 DPM1 1 4.2 29.2 260 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.5E+06 0.0E+00 subunit 1 26S proteasome non-ATPase regulatory 909 Q9WVJ2 PSMD13 1 4.0 42.8 376 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.1E+06 1.0E+06 subunit 13 Developmentally-regulated GTP-binding protein 910 Q9Y295 DRG1 2 5.7 40.5 367 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.8E+06 0.0E+00 1 911 Q9UBS4 DnaJ homolog subfamily B member 11 DNAJB11 1 4.5 40.5 358 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.7E+06 0.0E+00 912 P24638 Lysosomal acid phosphatase ACP2 1 2.8 48.5 423 6 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.7E+06 0.0E+00 913 Q9BYT8 Neurolysin, mitochondrial NLN 1 2.3 80.7 704 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.6E+06 0.0E+00 914 Q99N93 39S ribosomal protein L16, mitochondrial MRPL16 1 6.4 28.8 251 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.5E+06 0.0E+00 915 Q6IRU2 Tropomyosin alpha-4 chain TPM4 1 6.9 28.5 248 13 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.5E+06 0.0E+00 916 O55029 Coatomer subunit beta COPB2 1 2.1 102.5 905 8 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+06 0.0E+00 917 Q05920 Pyruvate carboxylase, mitochondrial PC 2 2.3 129.7 1178 7 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+06 0.0E+00 918 Q99LX0 Protein deglycase DJ-1 PARK7 1 10.1 20.0 189 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+06 0.0E+00 Pentatricopeptide repeat domain-containing 919 Q14C51 PTCD3 2 2.6 77.8 685 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+06 0.0E+00 protein 3, mitochondrial Aminoacyl tRNA synthase complex-interacting 920 Q8R010 AIMP2 1 2.8 35.4 320 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+06 0.0E+00 multifunctional protein 2 921 Q9BZG1 Ras-related protein Rab-34 RAB34 1 6.2 29.0 259 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.2E+06 0.0E+00 Medium-chain specific acyl-CoA 922 P45952 ACADM 3 11.9 46.5 421 14 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.1E+05 0.0E+00 dehydrogenase, mitochondrial Mitochondrial import inner membrane 923 O43615 TIMM44 1 2.4 51.4 452 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 7.7E+05 0.0E+00 translocase subunit TIM44 26S proteasome non-ATPase regulatory 924 Q99JI4 PSMD6 2 6.2 45.5 389 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 7.6E+05 0.0E+00 subunit 6 925 P97363 Serine palmitoyltransferase 2 SPTLC2 1 3.2 63.0 560 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.8E+05 0.0E+00 cAMP-dependent protein kinase type II-beta 926 P31324 PRKAR2B 1 3.8 46.2 416 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.7E+05 0.0E+00 regulatory subunit Translational activator of cytochrome c oxidase 927 Q8K0Z7 TACO1 1 6.1 32.3 294 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.3E+05 0.0E+00 1 928 Q9WUR2 Enoyl-CoA delta isomerase 2, mitochondrial ECI2 1 3.1 43.3 391 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.2E+05 0.0E+00 929 P68368 Tubulin alpha-4A chain TUBA4A 1 49.1 49.9 448 -2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.2E+05 0.0E+00 930 P63154 Crooked neck-like protein 1 CRNKL1 1 1.9 83.4 690 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.1E+05 0.0E+00 Hydroxymethylglutaryl-CoA synthase, 931 Q8JZK9 HMGCS1 1 3.5 57.6 520 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.7E+05 0.0E+00 cytoplasmic 932 Q9Y6X5 Bis(5-adenosyl)-triphosphatase ENPP4 ENPP4 1 2.2 51.6 453 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.9E+05 0.0E+00 933 Q96J84 Kin of IRRE-like protein 1 KIRREL 1 1.2 83.5 757 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+05 0.0E+00 934 Q9JL70 Fanconi anemia group A protein homolog FANCA 1 1.1 161.2 1439 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.0E+07 935 Q71UM5 40S ribosomal protein S27-like RPS27L 1 38.1 9.5 84 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.7E+07 936 Q3UBX0 Transmembrane protein 109 TMEM109 1 4.9 26.3 243 16 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.7E+07 Succinate dehydrogenase cytochrome b560 937 Q9CZB0 SDHC 2 12.4 18.4 169 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+07 subunit, mitochondrial 938 P60603 Reactive oxygen species modulator 1 ROMO1 1 21.5 8.2 79 19 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+07 939 P60060 Protein transport protein Sec61 subunit gamma SEC61G 1 17.6 7.7 68 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+07 940 Q5F285 Transmembrane protein 256 TMEM256 1 7.1 11.7 113 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+07 Mitochondrial import inner membrane 941 Q9Y5L4 TIMM13 1 14.7 10.5 95 15 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+07 translocase subunit Tim13 942 Q922E6 FAST kinase domain-containing protein 2 FASTKD2 1 2.8 78.9 689 -2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.2E+07 943 Q80Y14 Glutaredoxin-related protein 5, mitochondrial GLRX5 2 21.7 16.3 152 14 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.1E+07 944 Q15836 Vesicle-associated membrane protein 3 VAMP3 1 17.0 11.3 100 49 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.1E+07 945 P21956 Lactadherin MFGE8 2 5.0 51.2 463 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.0E+07 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

946 Q5RL79 Keratinocyte-associated protein 2 KRTCAP2 1 12.5 14.7 136 37 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.2E+06 NADH dehydrogenase [ubiquinone] 1 alpha 947 Q9CQ75 NDUFA2 1 14.1 10.9 99 15 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.2E+06 subcomplex subunit 2 948 P62942 Peptidyl-prolyl cis-trans isomerase FKBP1A FKBP1A 1 12.0 12.0 108 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.9E+06 rRNA/tRNA 2-O-methyltransferase fibrillarin-like 949 Q80WS3 FBLL1 1 11.5 33.3 314 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.8E+06 protein 1 Mitochondrial import inner membrane 950 Q9CQV7 DNAJC19 2 28.4 12.4 116 8 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.4E+06 translocase subunit TIM14 951 Q9D1G1 Ras-related protein Rab-1B RAB1B 1 31.8 22.2 201 9 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.4E+06 Cytochrome c oxidase subunit 7A2, 952 P48771 COX7A2 1 12.0 9.3 83 6 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.3E+06 mitochondrial Solute carrier family 2, facilitated glucose 953 P17809 SLC2A1 1 1.6 54.0 492 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.5E+06 transporter member 1 954 Q9CPP0 Nucleoplasmin-3 NPM3 1 9.1 19.0 175 27 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.3E+06 955 Q8BXV2 BRI3-binding protein BRI3BP 1 7.5 28.3 253 28 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.0E+06 Dolichol-phosphate mannosyltransferase 956 Q9D1Q4 DPM3 1 10.9 10.1 92 6 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.0E+06 subunit 3 957 P08556 GTPase NRas NRAS 4 30.2 21.2 189 6 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.9E+06 958 Q9QYF1 Retinol dehydrogenase 11 RDH11 1 4.1 35.1 316 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.9E+06 959 P47962 60S ribosomal protein L5 RPL5 1 6.1 34.4 297 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.9E+06 Testis- and ovary-specific PAZ domain- 960 E5FYH1 TOPAZ1 1 0.7 185.5 1653 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.9E+06 containing protein 1 ATP-dependent Clp protease proteolytic 961 O88696 CLPP 1 6.6 29.8 272 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.7E+06 subunit, mitochondrial 962 Q9JLI6 Selenocysteine lyase SCLY 1 2.8 47.2 432 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.7E+06 Mitochondrial import inner membrane 963 Q9WTQ8 TIMM23 1 8.1 22.0 209 9 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.5E+06 translocase subunit Tim23 964 Q9R1P3 Proteasome subunit beta type-2 PSMB2 1 5.5 22.9 201 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.4E+06 965 P43487 Ran-specific GTPase-activating protein RANBP1 1 5.5 23.3 201 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.3E+06 966 Q99J93 Interferon-induced transmembrane protein 2 IFITM2 1 11.1 15.7 144 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.3E+06 967 P45878 Peptidyl-prolyl cis-trans isomerase FKBP2 FKBP2 1 10.7 15.3 140 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.1E+06 968 Q6EEV6 Small ubiquitin-related modifier 4 SUMO4 1 12.6 10.7 95 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.1E+06 969 Q9CPT4 Myeloid-derived growth factor MYDGF 1 5.4 18.0 166 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.0E+06 970 Q9QUM9 Proteasome subunit alpha type-6 PSMA6 1 5.3 27.4 246 6 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.9E+06 971 Q06830 Peroxiredoxin-1 PRDX1 1 34.7 22.1 199 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.9E+06 972 Q6ZWX6 Eukaryotic translation initiation factor 2 subunit 1 EIF2S1 2 8.6 36.1 315 17 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.6E+06 973 Q3UMR5 Calcium uniporter protein, mitochondrial MCU 2 10.0 39.7 350 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.4E+06 Transmembrane emp24 domain-containing 974 Q9R0Q3 TMED2 1 6.5 22.7 201 10 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.2E+06 protein 2 975 Q99714 3-hydroxyacyl-CoA dehydrogenase type-2 HSD17B10 1 14.2 26.9 261 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.2E+06 976 P97324 Glucose-6-phosphate 1-dehydrogenase 2 G6PD2 1 1.9 59.1 513 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.1E+06 977 Q9R1P1 Proteasome subunit beta type-3 PSMB3 1 7.8 23.0 205 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.1E+06 NFU1 iron-sulfur cluster scaffold homolog, 978 Q9UMS0 NFU1 1 5.1 28.5 254 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.0E+06 mitochondrial Supplementary file 4A : (continued) 979 P58059 28S ribosomal protein S21, mitochondrial MRPS21 1 14.9 10.6 87 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.9E+06 980 Q9JII6 Alcohol dehydrogenase [NADP(+)] AKR1A1 1 3.7 36.6 325 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.8E+06 981 O55128 Histone deacetylase complex subunit SAP18 SAP18 1 10.5 17.6 153 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.8E+06 982 Q61469 Lipid phosphate phosphohydrolase 1 PPAP2A 1 7.1 31.9 283 9 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.7E+06 983 Q96CD2 Phosphopantothenoylcysteine decarboxylase PPCDC 1 7.8 22.4 204 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.5E+06 984 P47753 F-actin-capping protein subunit alpha-1 CAPZA1 1 8.7 32.9 286 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.5E+06 NADH dehydrogenase [ubiquinone] 1 beta 985 Q9CQH3 NDUFB5 1 5.8 21.7 189 20 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.5E+06 subcomplex subunit 5, mitochondrial 986 Q9WV54 Acid ceramidase ASAH1 1 4.6 44.7 394 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.5E+06 987 A6NCN2 Putative keratin-87 protein KRT87P 2 11.4 29.1 255 6 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.5E+06 988 P14416 D(2) dopamine receptor DRD2 1 2.3 50.6 443 -2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.5E+06 989 Q7Z3B0 Small integral membrane protein 15 SMIM15 1 16.2 8.6 74 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.3E+06 990 Q3TBW2 39S ribosomal protein L10, mitochondrial MRPL10 1 7.3 29.4 262 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.2E+06 991 O08795 Glucosidase 2 subunit beta PRKCSH 1 1.9 58.8 521 7 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.2E+06 Isocitrate dehydrogenase [NAD] subunit beta, 992 O43837 IDH3B 1 2.6 42.2 385 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.2E+06 mitochondrial 993 Q9CQ71 Replication protein A 14 kDa subunit RPA3 2 24.0 13.6 121 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.1E+06 994 Q9Y333 U6 snRNA-associated Sm-like protein LSm2 LSM2 1 20.0 10.8 95 19 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.9E+06 995 Q9CXY9 GPI-anchor transamidase PIGK 1 3.0 44.9 395 13 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.8E+06 996 Q9H307 Pinin PNN 2 3.3 81.6 717 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.8E+06 997 Q9QZD8 Mitochondrial dicarboxylate carrier SLC25A10 1 8.4 31.7 287 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.8E+06 998 Q80X85 28S ribosomal protein S7, mitochondrial MRPS7 1 5.4 28.1 242 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.7E+06 999 Q9R0Q7 Prostaglandin E synthase 3 PTGES3 1 7.5 18.7 160 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.7E+06 1000 Q8WXX0 Dynein heavy chain 7, axonemal DNAH7 2 0.5 461.2 4024 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.7E+06 1001 Q9R1P0 Proteasome subunit alpha type-4 PSMA4 1 3.8 29.5 261 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.6E+06 1002 Q9CQ22 Ragulator complex protein LAMTOR1 LAMTOR1 1 8.1 17.7 161 17 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.6E+06 1003 P34932 Heat shock 70 kDa protein 4 HSPA4 2 3.9 94.3 840 10 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.6E+06 1004 P28798 Granulins GRN 2 5.1 63.5 589 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.6E+06 NADH dehydrogenase [ubiquinone] flavoprotein 1005 Q9D6J6 NDUFV2 1 4.0 27.3 248 19 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.6E+06 2, mitochondrial 1006 Q9ERE7 LDLR chaperone MESD MESDC2 1 4.5 25.2 224 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.5E+06 1007 Q9R0P5 Destrin DSTN 1 9.7 18.5 165 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.5E+06 1008 Q9CRB2 H/ACA ribonucleoprotein complex subunit 2 NHP2 1 10.5 17.2 153 13 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.5E+06 1009 P23528 Cofilin-1 CFL1 1 52.4 18.5 166 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.5E+06 1010 Q80ZS3 28S ribosomal protein S26, mitochondrial MRPS26 1 9.0 23.4 200 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.5E+06 NADH dehydrogenase [ubiquinone] 1 alpha 1011 Q9D8B4 NDUFA11 1 7.8 15.0 141 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.5E+06 subcomplex subunit 11 1012 P54227 Stathmin STMN1 1 8.7 17.3 149 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.4E+06 1013 P31786 Acyl-CoA-binding protein DBI 1 8.0 10.0 87 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.4E+06 LETM1 and EF-hand domain-containing protein 1014 Q9Z2I0 LETM1 1 1.9 83.0 738 21 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.3E+06 1, mitochondrial Transmembrane and TPR repeat-containing 1015 Q8BRH0 TMTC3 2 2.7 104.2 920 32 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.3E+06 protein 3 1016 Q9JHJ3 Glycosylated lysosomal membrane protein GLMP 1 3.2 43.8 404 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.2E+06 1017 O35326 Serine/arginine-rich splicing factor 5 SRSF5 1 3.3 30.9 269 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.1E+06 1018 Q9D3P8 Plasminogen receptor (KT) PLGRKT 1 6.8 17.3 147 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.1E+06 1019 P54116 Erythrocyte band 7 integral membrane protein STOM 1 5.6 31.4 284 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.1E+06 NADH dehydrogenase [ubiquinone] iron-sulfur 1020 Q99LY9 NDUFS5 1 11.3 12.6 106 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.0E+06 protein 5 1021 Q99653 Calcineurin B homologous protein 1 CHP1 1 6.2 22.5 195 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.0E+06 1022 Q8R2L5 28S ribosomal protein S18c, mitochondrial MRPS18C 1 13.3 16.3 143 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.0E+06 1023 P14873 Microtubule-associated protein 1B MAP1B 1 0.6 270.3 2464 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.0E+06 1024 P38060 Hydroxymethylglutaryl-CoA lyase, mitochondrial HMGCL 1 4.3 34.2 325 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.9E+06 1025 Q8BGP6 Solute carrier family 25 member 40 SLC25A40 2 7.7 38.0 337 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.9E+06 3-hydroxyisobutyrate dehydrogenase, 1026 Q99L13 HIBADH 1 4.2 35.4 335 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.9E+06 mitochondrial 1027 Q8BGX0 E3 ubiquitin-protein ligase TRIM23 TRIM23 1 1.7 63.9 574 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.8E+06 1028 P19157 Glutathione S-transferase P 1 GSTP1 1 5.2 23.6 210 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.8E+06 1029 P16254 Signal recognition particle 14 kDa protein SRP14 1 12.7 12.5 110 15 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.8E+06 1030 O88455 7-dehydrocholesterol reductase DHCR7 1 2.3 53.9 471 8 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.7E+06 1031 Q9QXT0 Protein canopy homolog 2 CNPY2 1 6.6 20.8 182 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.7E+06 Deoxyuridine 5-triphosphate 1032 P33316 DUT 1 4.8 26.6 252 10 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.7E+06 nucleotidohydrolase, mitochondrial 1033 Q99832 T-complex protein 1 subunit eta CCT7 1 2.6 59.4 543 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.7E+06 1034 Q9Y3B4 Splicing factor 3B subunit 6 SF3B6 1 11.2 14.6 125 9 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.6E+06 1035 O88653 Ragulator complex protein LAMTOR3 LAMTOR3 1 8.9 13.6 124 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.6E+06 1036 Q59J78 Mimitin, mitochondrial NDUFAF2 1 4.8 19.6 168 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.6E+06 1037 Q96PU5 E3 ubiquitin-protein ligase NEDD4-like NEDD4L 1 3.3 111.9 975 14 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.5E+06 1038 Q99N87 28S ribosomal protein S5, mitochondrial MRPS5 1 3.2 48.2 432 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.5E+06 Cytochrome c oxidase assembly protein 1039 Q8BJ03 COX15 1 3.6 45.9 413 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.5E+06 COX15 homolog 1040 Q9CQM9 Glutaredoxin-3 GLRX3 3 16.3 37.8 337 12 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+06 Hypoxanthine-guanine 1041 P00493 HPRT1 1 4.6 24.6 218 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+06 phosphoribosyltransferase 1042 P02468 Laminin subunit gamma-1 LAMC1 1 0.9 177.3 1607 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+06 1043 Q8N8Y2 V-type proton ATPase subunit d 2 ATP6V0D2 1 4.3 40.4 350 39 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+06 1044 Q64727 Vinculin VCL 1 2.0 116.7 1066 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+06 1045 Q9CZD3 Glycine--tRNA ligase GARS 1 1.8 81.9 729 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+06 Plasminogen activator inhibitor 1 RNA-binding 1046 Q9CY58 SERBP1 1 3.9 44.7 407 9 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.4E+06 protein 1047 P19367 Hexokinase-1 HK1 1 7.5 102.5 917 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+06 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

1048 Q13547 Histone deacetylase 1 HDAC1 1 2.5 55.1 482 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+06 1049 Q9UBG0 C-type mannose receptor 2 MRC2 1 0.9 166.7 1479 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+06 1050 P97384 Annexin A11 ANXA11 1 1.8 54.1 503 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+06 1051 P08030 Adenine phosphoribosyltransferase APRT 1 11.1 19.7 180 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.3E+06 Adipocyte plasma membrane-associated 1052 Q9D7N9 APMAP 1 6.5 46.4 415 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.2E+06 protein 1053 P61006 Ras-related protein Rab-8A RAB8A 1 12.1 23.7 207 15 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.2E+06 Eukaryotic translation initiation factor 3 subunit 1054 Q8JZQ9 EIF3B 1 1.6 91.4 803 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.2E+06 B Activator of 90 kDa heat shock protein ATPase 1055 Q8BK64 AHSA1 1 6.5 38.1 338 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.2E+06 homolog 1 1056 Q9D8S4 Oligoribonuclease, mitochondrial REXO2 1 7.6 26.7 237 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.2E+06 1057 P07214 SPARC SPARC 1 5.3 34.5 302 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.2E+06 1058 P97429 Annexin A4 ANXA4 1 5.0 35.9 319 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.1E+06 1059 Q9H4I9 Essential MCU regulator, mitochondrial SMDT1 1 15.9 11.4 107 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.1E+06 Guanine nucleotide-binding protein subunit 1060 Q14344 GNA13 1 2.7 44.0 377 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.1E+06 alpha-13 1061 Q9WUA2 Phenylalanine--tRNA ligase beta subunit FARSB 1 2.2 65.7 589 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.1E+06 1062 Q9UKD2 mRNA turnover protein 4 homolog MRTO4 1 4.2 27.6 239 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.1E+06 1063 P84085 ADP-ribosylation factor 5 ARF5 1 42.2 20.5 180 -2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.0E+06 1064 Q9ERR7 15 kDa selenoprotein Sep-15 1 9.9 17.8 162 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.0E+06 1065 Q3TDN2 FAS-associated factor 2 FAF2 3 10.1 52.5 445 9 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.0E+06 1066 Q9ERK4 Exportin-2 CSE1L 2 2.4 110.5 971 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.0E+06 1067 Q99M28 RNA-binding protein with serine-rich domain 1 RNPS1 1 4.9 34.2 305 9 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.0E+06

1068 Q8WWC4 Uncharacterized protein C2orf47, mitochondrial C2ORF47 1 3.4 32.5 291 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.0E+06 Very long-chain specific acyl-CoA 1069 P49748 ACADVL 1 2.6 70.4 655 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.8E+05 dehydrogenase, mitochondrial Platelet-activating factor acetylhydrolase IB 1070 Q61206 PAFAH1B2 1 3.9 25.6 229 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.7E+05 subunit beta 1071 Q9HCD5 Nuclear receptor coactivator 5 NCOA5 1 3.1 65.5 579 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.7E+05 Short/branched chain specific acyl-CoA 1072 Q9DBL1 ACADSB 1 5.1 47.9 432 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.6E+05 dehydrogenase, mitochondrial Elongation of very long chain fatty acids protein 1073 Q9JLJ5 ELOVL1 1 4.7 32.7 279 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.6E+05 1 Mitochondrial-processing peptidase subunit 1074 Q9DC61 PMPCA 1 3.2 58.3 524 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.4E+05 alpha 1075 Q9WVK4 EH domain-containing protein 1 EHD1 1 1.7 60.6 534 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.3E+05 1076 Q58FF6 Putative heat shock protein HSP 90-beta 4 HSP90AB4P 1 9.5 58.3 505 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 9.1E+05 1077 Q8R5C5 Beta-centractin ACTR1B 1 4.3 42.3 376 8 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.8E+05 1078 Q8NEV1 Casein kinase II subunit alpha 3 CSNK2A3 1 4.9 45.2 391 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.7E+05 1079 Q8VE10 N-alpha-acetyltransferase 40 NAA40 1 5.1 27.2 237 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.6E+05 1080 O88967 ATP-dependent zinc metalloprotease YME1L1 YME1L1 2 4.9 80.0 715 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.3E+05

1081 Q8K0V4 CCR4-NOT transcription complex subunit 3 CNOT3 1 1.3 81.9 751 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.3E+05 1082 Q99LS3 Phosphoserine phosphatase PSPH 1 5.3 25.1 225 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.2E+05 1083 P51807 Dynein light chain Tctex-type 1 DYNLT1 1 15.9 12.5 113 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.2E+05 1084 Q9NVH1 DnaJ homolog subfamily C member 11 DNAJC11 1 3.6 63.3 559 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 8.1E+05 1085 Q32P28 Prolyl 3-hydroxylase 1 LEPRE1 1 1.6 83.4 736 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 7.8E+05 1086 Q9D6M3 Mitochondrial glutamate carrier 1 SLC25A22 1 6.2 34.7 323 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 7.7E+05 Supplementary file 4A : (continued) 1087 Q9NYL9 Tropomodulin-3 TMOD3 1 6.0 39.6 352 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 7.3E+05 1088 Q8VHY0 Chondroitin sulfate proteoglycan 4 CSPG4 1 0.9 252.3 2327 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 7.0E+05 1089 Q96HY6 DDRGK domain-containing protein 1 DDRGK1 1 5.4 35.6 314 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.8E+05 1090 Q92882 Osteoclast-stimulating factor 1 OSTF1 1 5.6 23.8 214 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.7E+05 1091 Q93092 Transaldolase TALDO1 1 3.3 37.4 337 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.6E+05 1092 Q99KE1 NAD-dependent malic enzyme, mitochondrial ME2 1 3.1 65.8 589 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.5E+05

1093 O54692 Centromere/kinetochore protein zw10 homolog ZW10 1 2.1 88.1 779 7 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.3E+05

1094 P35922 Fragile X mental retardation protein 1 homolog FMR1 1 2.3 69.0 614 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.2E+05 1095 P97310 DNA replication licensing factor MCM2 MCM2 3 4.1 102.1 904 7 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.2E+05 1096 Q9R0A0 Peroxisomal membrane protein PEX14 PEX14 1 2.7 41.2 376 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.1E+05 1097 Q8BYL4 Tyrosine--tRNA ligase, mitochondrial YARS2 1 2.5 52.6 472 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.0E+05 1098 Q9EPU0 Regulator of nonsense transcripts 1 UPF1 1 1.0 124.0 1124 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 6.0E+05 1099 Q9JIF7 Coatomer subunit beta COPB1 3 3.7 107.1 953 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.9E+05 Evolutionarily conserved signaling intermediate 1100 Q9QZH6 ECSIT 1 3.2 49.8 435 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.8E+05 in Toll pathway, mitochondrial 1101 O08529 Calpain-2 catalytic subunit CAPN2 1 1.6 79.9 700 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.8E+05 Fragile X mental retardation syndrome-related 1102 P51114 FXR1 2 3.5 69.7 621 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.8E+05 protein 1 1103 A2AR02 Peptidyl-prolyl cis-trans isomerase G PPIG 1 1.6 88.3 752 4 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.7E+05 1104 Q80ZK0 28S ribosomal protein S10, mitochondrial MRPS10 1 9.4 18.7 160 6 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.7E+05 Signal peptidase complex catalytic subunit 1105 Q9D8V7 SEC11C 1 5.2 21.7 192 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 5.6E+05 SEC11C 1106 P35659 Protein DEK DEK 1 3.2 42.7 375 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.9E+05 1107 O35841 Apoptosis inhibitor 5 API5 1 3.6 56.8 504 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.7E+05 Serine/threonine-protein phosphatase PP1- 1108 P62137 PPP1CA 1 31.2 37.5 330 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.6E+05 alpha catalytic subunit 1109 Q9EPK2 Protein XRP2 RP2 1 2.9 39.4 347 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.4E+05 1110 Q6P542 ATP-binding cassette sub-family F member 1 ABCF1 1 1.2 94.9 837 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.3E+05 1111 Q9CZU4 GTPase Era, mitochondrial ERAL1 1 3.0 48.2 437 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.2E+05 1112 Q9D0G0 28S ribosomal protein S30, mitochondrial MRPS30 1 2.9 49.9 442 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 4.2E+05 1113 P10518 Delta-aminolevulinic acid dehydratase ALAD 1 4.8 36.0 330 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.9E+05 1114 Q6PGH1 Protein BUD31 homolog BUD31 1 6.9 17.0 144 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 3.2E+05 1115 Q921S7 39S ribosomal protein L37, mitochondrial MRPL37 1 3.3 48.3 423 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.9E+05 1116 Q8N766 ER membrane protein complex subunit 1 EMC1 1 11.1 111.8 993 -2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.8E+05 1117 Q9H0S4 Probable ATP-dependent RNA helicase DDX47 DDX47 1 4.0 50.6 455 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.7E+05 1118 P61750 ADP-ribosylation factor 4 ARF4 1 46.7 20.4 180 5 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.4E+05 1119 Q810D6 Glutamate-rich WD repeat-containing protein 1 GRWD1 1 3.6 49.2 446 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 2.1E+05 1120 P97386 DNA ligase 3 LIG3 1 1.0 113.1 1015 2 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.7E+05 1121 Q9JMH6 Thioredoxin reductase 1, cytoplasmic TXNRD1 1 2.4 67.1 613 3 0.0E+00 0.0E+00 0.0E+00 0.0E+00 0.0E+00 1.6E+05 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Supplementary file 4B : The degree of variances in the proteome between the biological replicates and groups assessed by Pearson's correlation analysis bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Supplementary file 4C: Differentially expressed proteins in OxSR cells compared to HT22-WT cell line

Majority protein Student's T-test p- Student's T-test q- Student's T-test Student's T-test Protein names Gene names IDs value value Difference Test statistic

P11087 Collagen alpha-1(I) chain COL1A1 1.01E-04 0.00E+00 -5.26 -15.49 Q01149 Collagen alpha-2(I) chain COL1A2 4.03E-03 1.62E-02 -3.89 -5.94 P28301 Protein-lysine 6-oxidase LOX 5.68E-04 0.00E+00 -3.21 -9.97 O54724 Polymerase I and transcript release factor PTRF 4.05E-03 1.59E-02 -2.88 -5.93 P27048 Small nuclear ribonucleoprotein-associated protein B SNRPB 1.06E-02 2.53E-02 -2.42 -4.53 P29533 Vascular cell adhesion protein 1 VCAM1 1.38E-02 2.91E-02 -2.32 -4.19 O35682 Myeloid-associated differentiation marker MYADM 1.68E-03 2.59E-03 -2.28 -7.52 Q8WVC6 Dephospho-CoA kinase domain-containing protein DCAKD 1.84E-03 4.82E-03 -2.10 -7.33 Q91ZX7 Prolow-density lipoprotein receptor-related protein 1 LRP1 1.24E-02 2.99E-02 -2.10 -4.32 Q9Z110 Delta-1-pyrroline-5-carboxylate synthase ALDH18A1 4.15E-03 1.57E-02 -2.04 -5.89 Q9QYR9 Acyl-coenzyme A thioesterase 2, mitochondrial ACOT2 2.48E-02 5.00E-02 -2.02 -3.50 Succinyl-CoA ligase [GDP-forming] subunit beta, Q9Z2I8 SUCLG2 5.53E-04 0.00E+00 -1.90 -10.04 mitochondrial Bifunctional methylenetetrahydrofolate P18155 MTHFD2 2.11E-02 4.08E-02 -1.89 -3.68 dehydrogenase/cyclohydrol Q99KP6 Pre-mRNA-processing factor 19 PRPF19 9.63E-03 2.47E-02 -1.88 -4.65 Q6ZWQ7 Signal peptidase complex subunit 3 SPCS3 1.26E-02 2.95E-02 -1.82 -4.30 Q80UM7 Mannosyl-oligosaccharide glucosidase MOGS 1.94E-04 0.00E+00 -1.80 -13.13 P19324 Serpin H1 SERPINH1 3.63E-03 1.78E-02 -1.73 -6.11 Q61543 Golgi apparatus protein 1 GLG1 5.19E-05 0.00E+00 -1.72 -18.35 P16546 Spectrin alpha chain, non-erythrocytic 1 SPTAN1 1.64E-02 3.25E-02 -1.71 -3.98 Q8K009 Mitochondrial 10-formyltetrahydrofolate dehydrogenase ALDH1L2 8.57E-03 2.52E-02 -1.65 -4.81 P43406 Integrin alpha-V ITGAV 2.42E-02 5.00E-02 -1.54 -3.53 P00405 Cytochrome c oxidase subunit 2 MTCO2 8.31E-04 0.00E+00 -1.46 -9.04 Q62261 Spectrin beta chain, non-erythrocytic 1 SPTBN1 2.43E-02 4.97E-02 -1.36 -3.53 Q99K85 Phosphoserine aminotransferase PSAT1 7.63E-03 2.46E-02 -1.33 -4.97 P27659 60S ribosomal protein L3 RPL3 1.02E-02 2.63E-02 -1.32 -4.58 O89086 RNA-binding protein 3 RBM3 1.03E-02 2.60E-02 -1.32 -4.56 Q3U7R1 Extended synaptotagmin-1 ESYT1 2.21E-02 4.34E-02 -1.32 -3.63 P10852 4F2 cell-surface antigen heavy chain SLC3A2 4.93E-07 0.00E+00 -1.30 -59.05 Phosphoenolpyruvate carboxykinase [GTP], Q8BH04 PCK2 1.88E-03 4.70E-03 -1.27 -7.30 mitochondrial P27046 Alpha-mannosidase 2 MAN2A1 1.29E-02 3.02E-02 -1.24 -4.27 Q8R081 Heterogeneous nuclear ribonucleoprotein L HNRNPL 1.26E-02 2.97E-02 -1.23 -4.31 P31943 Heterogeneous nuclear ribonucleoprotein H HNRNPH1 1.21E-02 2.94E-02 -1.18 -4.36 Q8BP67 60S ribosomal protein L24 RPL24 5.06E-03 1.90E-02 -1.16 -5.58 P14733 Lamin-B1 LMNB1 1.31E-03 3.00E-03 -1.15 -8.02 P43276 Histone H1.5 HIST1H1B 2.63E-04 0.00E+00 -1.11 -12.15 P03975 IgE-binding protein IAP 6.63E-03 2.45E-02 -1.10 -5.17 P29758 Ornithine aminotransferase, mitochondrial OAT 5.10E-03 1.88E-02 -1.10 -5.57 P17427 AP-2 complex subunit alpha-2 AP2A2 7.13E-03 2.43E-02 -1.09 -5.07 P43277 Histone H1.3 HIST1H1D 4.58E-03 1.66E-02 -1.07 -5.73 Q9CR57 60S ribosomal protein L14 RPL14 7.98E-03 2.52E-02 -1.05 -4.91 P58742 Aladin AAAS 2.45E-02 5.06E-02 -1.05 -3.52 Q921F2 TAR DNA-binding protein 43 TARDBP 2.68E-04 0.00E+00 -1.02 -12.10 P15864 Histone H1.2 HIST1H1C 4.21E-04 0.00E+00 -0.91 -10.77 Q9CQS8 Protein transport protein Sec61 subunit beta SEC61B 2.74E-03 1.40E-02 -0.91 -6.60 Vacuolar ATPase assembly integral membrane protein Q78T54 VMA21 7.04E-04 0.00E+00 -0.89 -9.43 Vma21 P61979 Heterogeneous nuclear ribonucleoprotein K HNRNPK 1.54E-02 3.25E-02 -0.88 -4.05 Q9BVK6 Transmembrane emp24 domain-containing protein 9 TMED9 7.67E-04 0.00E+00 -0.83 -9.23 P51150 Ras-related protein Rab-7a RAB7A 3.17E-03 1.97E-02 -0.80 -6.34 P10922 Histone H1.0 H1F0 9.52E-03 2.52E-02 -0.79 -4.67 P63261 Actin, cytoplasmic 2 ACTG1 9.65E-04 3.56E-03 -0.78 -8.69 P46935 E3 ubiquitin-protein ligase NEDD4 NEDD4 8.55E-03 2.55E-02 -0.77 -4.82 Q9CZN7 Serine hydroxymethyltransferase SHMT2 2.65E-02 5.04E-02 -0.76 -3.43 Q9CX86 Heterogeneous nuclear ribonucleoprotein A0 HNRNPA0 1.90E-02 3.51E-02 -0.74 -3.81 Q9DCN2 NADH-cytochrome b5 reductase 3 CYB5R3 3.40E-03 1.87E-02 -0.73 -6.22 Q61024 Asparagine synthetase [glutamine-hydrolyzing] ASNS 7.14E-03 2.40E-02 -0.73 -5.07 P60710 Actin, cytoplasmic 1 ACTB 2.70E-03 1.43E-02 -0.72 -6.62 Q61335 B-cell receptor-associated protein 31 BCAP31 5.11E-03 1.85E-02 -0.72 -5.57 Q9QZQ8 Core histone macro-H2A.1 H2AFY 1.45E-02 2.93E-02 -0.71 -4.13 Q9UQ80 Proliferation-associated protein 2G4 PA2G4 1.48E-02 3.07E-02 -0.69 -4.10 Q60668 Heterogeneous nuclear ribonucleoprotein D0 HNRNPD 9.06E-03 2.57E-02 -0.68 -4.74 Q9DB77 Cytochrome b-c1 complex subunit 2, mitochondrial UQCRC2 3.51E-03 1.84E-02 -0.68 -6.17 Q8BFR4 N-acetylglucosamine-6-sulfatase GNS 2.47E-02 5.03E-02 -0.67 -3.51 P49312 Heterogeneous nuclear ribonucleoprotein A1 HNRNPA1 1.33E-02 2.93E-02 -0.67 -4.24 Q91VC3 Eukaryotic initiation factor 4A-III EIF4A3 3.28E-03 1.90E-02 -0.66 -6.28 Q8VDD5 Myosin-9 MYH9 2.11E-02 4.11E-02 -0.66 -3.69 P62806 Histone H4 HIST1H4A 5.29E-03 1.96E-02 -0.66 -5.51 Sterol-4-alpha-carboxylate 3-dehydrogenase, Q9R1J0 NSDHL 1.07E-02 2.51E-02 -0.63 -4.51 decarboxylating P14148 60S ribosomal protein L7 RPL7 2.20E-03 8.98E-03 -0.62 -6.99 P97351 40S ribosomal protein S3a RPS3A 1.44E-02 2.96E-02 -0.60 -4.14 P61421 V-type proton ATPase subunit d 1 ATP6V0D1 2.45E-03 1.10E-02 -0.60 -6.80 Q8VIJ6 Splicing factor, proline- and glutamine-rich SFPQ 2.56E-03 1.46E-02 -0.58 -6.72 Q60973 Histone-binding protein RBBP7 RBBP7 1.05E-02 2.58E-02 -0.55 -4.54 Q62186 Translocon-associated protein subunit delta SSR4 3.88E-03 1.64E-02 -0.55 -6.00 Q02248 Catenin beta-1 CTNNB1 9.86E-03 2.51E-02 -0.48 -4.62 P25444 40S ribosomal protein S2 RPS2 1.61E-02 3.30E-02 -0.47 -4.01 Q01320 DNA topoisomerase 2-alpha TOP2A 2.16E-02 4.31E-02 -0.45 -3.66 Q3U0V1 Far upstream element-binding protein 2 KHSRP 5.91E-04 0.00E+00 -0.43 -9.87 Q8VEK3 Heterogeneous nuclear ribonucleoprotein U HNRNPU 1.80E-02 3.47E-02 -0.41 -3.87 Succinate dehydrogenase [ubiquinone] iron-sulfur Q9CQA3 SDHB 8.48E-03 2.44E-02 -0.41 -4.83 subunit, mitoch bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

P35279 Ras-related protein Rab-6A RAB6A 3.73E-03 1.72E-02 -0.40 -6.06 Supplementary file 4C: (continued) P09055 Integrin beta-1 ITGB1 2.59E-02 5.02E-02 -0.39 -3.46 Q64012 RNA-binding protein Raly RALY 1.07E-02 2.49E-02 -0.37 -4.51 Q9WTP6 Adenylate kinase 2, mitochondrial AK2 6.79E-03 2.52E-02 -0.36 -5.14 Monofunctional C1-tetrahydrofolate synthase, Q3V3R1 MTHFD1L 2.39E-02 4.95E-02 -0.36 -3.55 mitochondrial P61255 60S ribosomal protein L26 RPL26 1.63E-03 2.82E-03 -0.36 -7.57 Q02543 60S ribosomal protein L18a RPL18A 9.04E-03 2.59E-02 -0.34 -4.74 P99024 Tubulin beta-5 chain TUBB5 2.34E-02 4.79E-02 -0.33 -3.57 P62908 40S ribosomal protein S3 RPS3 1.51E-02 3.20E-02 -0.31 -4.08 P07356 Annexin A2 ANXA2 1.18E-02 2.85E-02 -0.25 -4.39 P16615 Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 ATP2A2 6.01E-03 2.13E-02 0.24 5.32 Q9CR67 Transmembrane protein 33 TMEM33 9.45E-03 2.54E-02 0.29 4.68 Q9CPR4 60S ribosomal protein L17 RPL17 2.53E-02 5.03E-02 0.31 3.48 Q922J9 Fatty acyl-CoA reductase 1 FAR1 4.28E-03 1.68E-02 0.40 5.84 Q9NP72 Ras-related protein Rab-18 RAB18 9.88E-03 2.59E-02 0.42 4.62 P47955 60S acidic ribosomal protein P1 RPLP1 1.06E-02 2.56E-02 0.44 4.53 Q9CQN1 Heat shock protein 75 kDa, mitochondrial TRAP1 6.91E-03 2.49E-02 0.49 5.11 Q922Q8 Leucine-rich repeat-containing protein 59 LRRC59 3.77E-03 1.69E-02 0.49 6.05 P80314 T-complex protein 1 subunit beta CCT2 1.62E-02 3.27E-02 0.50 3.99 Q68FD5 Clathrin heavy chain 1 CLTC 1.19E-02 2.91E-02 0.55 4.37 P63038 60 kDa heat shock protein, mitochondrial HSPD1 2.36E-02 4.84E-02 0.57 3.56 P58252 Elongation factor 2 EEF2 4.25E-03 1.70E-02 0.59 5.86 Pyruvate dehydrogenase E1 component subunit beta, Q9D051 PDHB 3.60E-03 1.81E-02 0.59 6.12 mitochondrial P57776 Elongation factor 1-delta EEF1D 2.12E-02 4.12E-02 0.62 3.68 P07091 Protein S100-A4 S100A4 1.44E-02 2.98E-02 0.64 4.14 P84090 Enhancer of rudimentary homolog ERH 2.70E-02 5.01E-02 0.65 3.41 Q8K363 ATP-dependent RNA helicase DDX18 DDX18 8.90E-03 2.62E-02 0.71 4.76 P09671 Superoxide dismutase [Mn], mitochondrial SOD2 1.20E-02 2.89E-02 0.72 4.37 Pyruvate dehydrogenase E1 component subunit alpha, P35486 PDHA1 3.86E-03 1.67E-02 0.72 6.01 somatic form, Q8BFR5 Elongation factor Tu, mitochondrial TUFM 1.60E-02 3.32E-02 0.74 4.01 Q8R2Y8 Peptidyl-tRNA hydrolase 2, mitochondrial PTRH2 7.47E-03 2.51E-02 0.77 5.00 Q9CPQ3 Mitochondrial import receptor subunit TOM22 homolog TOMM22 1.22E-02 3.02E-02 0.77 4.34 P17751 Triosephosphate isomerase TPI1 4.09E-04 0.00E+00 0.78 10.86 P35700 Peroxiredoxin-1 PRDX1 1.93E-02 3.63E-02 0.78 3.79 Q8QZT1 Acetyl-CoA acetyltransferase, mitochondrial ACAT1 7.89E-03 2.43E-02 0.79 4.93 Q9CR62 Mitochondrial 2-oxoglutarate/malate carrier protein SLC25A11 5.45E-03 1.92E-02 0.80 5.46 Cytochrome b-c1 complex subunit Rieske, Q9CR68 UQCRFS1 2.10E-02 4.13E-02 0.80 3.69 mitochondrial Alkyldihydroxyacetonephosphate synthase, Q8C0I1 AGPS 1.32E-02 2.97E-02 0.84 4.25 peroxisomal Q8VBT0 Thioredoxin-related transmembrane protein 1 TMX1 1.51E-02 3.13E-02 0.86 4.08 Q61699 Heat shock protein 105 kDa HSPH1 2.01E-03 4.48E-03 0.90 7.16 Q69ZN7 Myoferlin MYOF 4.09E-04 0.00E+00 0.92 10.86 O08749 Dihydrolipoyl dehydrogenase, mitochondrial DLD 7.00E-03 2.46E-02 0.95 5.10 O08756 3-hydroxyacyl-CoA dehydrogenase type-2 HSD17B10 1.02E-03 3.43E-03 0.95 8.56 P35282 Ras-related protein Rab-21 RAB21 2.43E-03 1.12E-02 0.95 6.81 Q8BIJ6 Isoleucine--tRNA ligase, mitochondrial IARS2 2.50E-03 1.27E-02 0.97 6.76 P52480 Pyruvate kinase PKM PKM 3.71E-03 1.75E-02 0.98 6.08 P16858 Glyceraldehyde-3-phosphate dehydrogenase GAPDH 5.75E-04 0.00E+00 0.99 9.94 P27773 Protein disulfide-isomerase A3 PDIA3 2.55E-02 5.00E-02 1.00 3.47 Q64521 Glycerol-3-phosphate dehydrogenase, mitochondrial GPD2 2.95E-03 1.61E-02 1.02 6.46 Q8JZU2 Tricarboxylate transport protein, mitochondrial SLC25A1 8.17E-04 0.00E+00 1.05 9.08 Q8BH59 Calcium-binding mitochondrial carrier protein Aralar1 SLC25A12 4.91E-04 0.00E+00 1.07 10.35 Q9JKR6 Hypoxia up-regulated protein 1 HYOU1 1.64E-02 3.23E-02 1.08 3.98 P32020 Non-specific lipid-transfer protein SCP2 6.68E-03 2.42E-02 1.08 5.16 Q15907 Ras-related protein Rab-11B RAB11B 2.09E-03 9.18E-03 1.09 7.09 Q791V5 Mitochondrial carrier homolog 2 MTCH2 9.40E-04 3.69E-03 1.11 8.75 Q8K0D5 Elongation factor G, mitochondrial GFM1 6.25E-03 2.11E-02 1.11 5.26 P62259 14-3-3 protein epsilon YWHAE 8.31E-03 2.47E-02 1.12 4.85 Q9WVA4 Transgelin-2 TAGLN2 2.57E-02 4.97E-02 1.12 3.46 O08709 Peroxiredoxin-6 PRDX6 3.05E-03 1.58E-02 1.13 6.41 Q60930 Voltage-dependent anion-selective channel protein 2 VDAC2 5.45E-04 0.00E+00 1.14 10.08 P17182 Alpha-enolase ENO1 9.59E-03 2.49E-02 1.20 4.66 P16110 Galectin-3 LGALS3 1.71E-03 2.53E-03 1.21 7.48 P07901 Heat shock protein HSP 90-alpha HSP90AA1 1.66E-03 2.67E-03 1.22 7.53 Dihydrolipoyllysine-residue acetyltransferase Q8BMF4 DLAT 5.24E-03 1.99E-02 1.24 5.52 component of pyruv Q64337 Sequestosome-1 SQSTM1 2.01E-02 3.79E-02 1.24 3.74 Q9WUR9 Adenylate kinase 4, mitochondrial AK4 1.08E-03 3.20E-03 1.26 8.43 Q99JY0 Trifunctional enzyme subunit beta, mitochondrial HADHB 9.77E-03 2.54E-02 1.28 4.63 Q8BMS1 Trifunctional enzyme subunit alpha, mitochondrial HADHA 7.50E-03 2.49E-02 1.29 5.00 P11438 Lysosome-associated membrane glycoprotein 1 LAMP1 3.23E-03 1.94E-02 1.33 6.31 Q9ES97 Reticulon-3 RTN3 9.89E-03 2.65E-02 1.37 4.62 Q8VCW8 Acyl-CoA synthetase family member 2, mitochondrial ACSF2 1.65E-03 2.74E-03 1.40 7.55 P08249 Malate dehydrogenase, mitochondrial MDH2 2.34E-03 8.78E-03 1.40 6.88 Q9DCD0 6-phosphogluconate dehydrogenase, decarboxylating PGD 5.38E-03 1.94E-02 1.40 5.48 UDP-N-acetylhexosamine pyrophosphorylase-like Q3TW96 UAP1L1 1.29E-03 3.10E-03 1.50 8.06 protein 1 Q9D3D9 ATP synthase subunit delta, mitochondrial ATP5D 2.23E-02 4.47E-02 1.53 3.62 Q9CQR4 Acyl-coenzyme A thioesterase 13 ACOT13 8.12E-03 2.50E-02 1.54 4.89 Q91WS0 CDGSH iron-sulfur domain-containing protein 1 CISD1 4.80E-03 1.80E-02 1.67 5.66 Q8CI59 Metalloreductase STEAP3 STEAP3 2.07E-03 6.51E-03 1.68 7.11 P51660 Peroxisomal multifunctional enzyme type 2 HSD17B4 5.57E-04 0.00E+00 1.75 10.02 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Isocitrate dehydrogenase [NAD] subunit alpha, Q9D6R2 IDH3A 8.18E-04 0.00E+00 1.77 9.07 mitochondrial Q01768 Nucleoside diphosphate kinase B NME2 8.36E-04 0.00E+00 1.82 9.02 Supplementary file 4C: (continued) Catechol O-methyltransferase domain-containing Q8BIG7 COMTD1 2.09E-02 4.13E-02 1.85 3.69 protein 1 O70252 Heme oxygenase 2 HMOX2 2.71E-02 4.99E-02 1.87 3.41 P05064 Fructose-bisphosphate aldolase A ALDOA 7.75E-04 0.00E+00 1.90 9.20 Q16799 Reticulon-1 RTN1 5.76E-03 2.04E-02 1.90 5.38 Q9D710 Thioredoxin-related transmembrane protein 2 TMX2 1.32E-02 2.95E-02 1.90 4.25 P45376 Aldose reductase AKR1B1 1.44E-03 2.91E-03 2.45 7.83 Q921E2 Ras-related protein Rab-31 RAB31 1.65E-02 3.21E-02 2.47 3.97 Q99LP6 GrpE protein homolog 1, mitochondrial GRPEL1 1.97E-02 3.73E-02 2.56 3.76 Transmembrane and coiled-coil domain-containing Q9UM00 TMCO1 2.17E-02 4.36E-02 2.61 3.66 protein 1 P63323 40S ribosomal protein S12 RPS12 1.30E-02 3.00E-02 2.68 4.26 P08228 Superoxide dismutase [Cu-Zn] SOD1 2.31E-02 4.82E-02 2.69 3.58 Q8BLF1 Neutral cholesterol ester hydrolase 1 NCEH1 2.10E-02 4.10E-02 2.71 3.69 Q9CR21 Acyl carrier protein, mitochondrial NDUFAB1 1.93E-03 4.59E-03 2.90 7.24 Q9CQW9 Interferon-induced transmembrane protein 3 IFITM3 1.05E-03 3.31E-03 3.39 8.50 Hydroxyacyl-coenzyme A dehydrogenase, Q61425 HADH 2.27E-02 4.51E-02 3.63 3.60 mitochondrial P15532 Nucleoside diphosphate kinase A NME1 7.17E-04 0.00E+00 4.58 9.39 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Supplementary file 4D: The detailed list of proteins in each group of different cellular functions indicated in Figure 5B Functional Categories p- Value Proteins Total proteins Annotation Cell survival of 6.90E-04 ↓CTNNB1, ↑SOD2, ↓TARDBP 3 35 neurons Autophagic cell 1.14E-03 ↑LAMP1, ↑SOD1, ↑SOD2 3 death

↓CTNNB1, ↑GAPDH, ↑HMOX2, ↑HSD17B10, ↑HSPD1, ↑HSPH1, ↑HYOU1, Neuronal cell 2.21E-03 ↓ITGB1, ↑LGALS3, ↑LRP1, ↑PDIA3, ↓RPS3, 17 death ↓SDHB, ↑SLC25A12, ↑SOD1, ↑SOD2, Autophagy and ↓TARDBP neuronal stress ↑ATP2A2, ↑HSP90AA1, ↑HSPD1, ↑HSPH1, Endoplasmic ↑HYOU1, ↓RAB6A, ↑RTN1, ↓SERPINH1, reticulum stress 7.84E-09 13 ↑SOD1, ↑SQSTM1, ↑TMCO1, ↑TMEM33, response ↑TMX1

↑CISD1, ↑CLTC, ↓CTNNB1, ↑EEF2, ↑HSP90AA1, ↑LAMP1, ↑PKM, ↓RAB7A, Autophagy 3.79E-04 14 ↓SDHB, ↓SERPINH1, ↑SOD1, ↑SOD2, ↑SQSTM1, ↑TUFM

↑GPD2, ↑HSD17B10, ↑LGALS3, ↑PDHA1, Oxidative stress 5.82E-06 7 21 ↑SOD1, ↑SOD2, ↑SQSTM1

Reactive ↓ACTB, ↑AKR1B1, ↓ANXA2, ↓H2AFY, oxygen species Synthesis of ↓HNRNPK, ↑HSD17B10, ↓ITGB1, reactive oxygen 1.71E-06 ↑LGALS3, ↓LRP1, ↑PRDX1, ↑PRDX6, 19 species ↓RPL26, ↑SOD1, ↑SOD2, ↑SQSTM1, ↑TRAP1, ↓UQCRC2, ↑UQCRFS1, ↓VCAM1

↑ACAT1, ↓ACOT2, ↑AKR1B1, ↓CTNNB1, ↑DLAT, ↑DLD, ↑FAR1, ↑HMOX2, Fatty acid ↑HSD17B4, ↓ITGAV, ↓LRP1, ↑MDH2, 1.51E-06 21 35 metabolism ↑NCEH1, ↑PDHA1, ↑PDHB, ↑PKM, ↑PRDX6, ↑SCP2, ↓SDHB, ↑SOD1, ↓SUCLG2 Metabolism Glycolysis of ↑ALDOA, ↑CISD1, ↑ENO1, ↑GAPDH, 3.41E-06 9 cells ↑IDH3A, ↑MTCH2, ↑PDHA1, ↑PKM, ↑TPI1

↑DLAT, ↑DLD, ↑GFM1, ↑IARS2, ↓MT-CO2, Mitochondrial 4.35E-06 ↓PCK2, ↑PDHA1, ↑PDHB, ↑TUFM, 10 disorder ↓UQCRC2 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Supplementary file 4E: Protein-protein interactions network of the differentially expressed proteins in OxSR compared to HT22-WT as shown in Figure S2

From Molecule(s) Relationship Type To Molecule(s) Catalyst(s) CISD1 causation Autophagy CLTC causation Autophagy CTNNB1 causation Autophagy EEF2 causation Autophagy HSP90AA1 causation Autophagy LAMP1 causation Autophagy PKM causation Autophagy RAB7A causation Autophagy SDHB causation Autophagy SERPINH1 causation Autophagy SOD1 causation Autophagy SOD2 causation Autophagy SQSTM1 causation Autophagy TUFM causation Autophagy DLAT correlation Mitochondrial disorder DLD correlation Mitochondrial disorder GFM1 causation Mitochondrial disorder GFM1 correlation Mitochondrial disorder IARS2 causation Mitochondrial disorder MT-CO2 causation Mitochondrial disorder MT-CO2 correlation Mitochondrial disorder PCK2 causation Mitochondrial disorder PCK2 correlation Mitochondrial disorder PDHA1 causation Mitochondrial disorder PDHA1 correlation Mitochondrial disorder PDHB causation Mitochondrial disorder PDHB correlation Mitochondrial disorder TUFM causation Mitochondrial disorder TUFM correlation Mitochondrial disorder UQCRC2 causation Mitochondrial disorder GPD2 causation Oxidative stress HSD17B10 causation Oxidative stress LGALS3 causation Oxidative stress PDHA1 causation Oxidative stress SOD1 causation Oxidative stress SOD2 causation Oxidative stress SQSTM1 causation Oxidative stress CCT2 protein-protein interactions ACTB CTNNB1 expression ACTB HNRNPU protein-DNA interactions ACTB SOD1 protein-protein interactions ACTB TAGLN2 protein-protein interactions ACTB BAG3 protein-protein interactions AK2 PKM protein-protein interactions AK2 ANXA2 protein-protein interactions ANXA2 BAG3 protein-protein interactions ANXA2 HSPA1A/HSPA1B protein-protein interactions CLTC CTNNB1 expression COL1A1 CTNNB1 expression CTNNB1 HIST1H1C protein-protein interactions CTNNB1 HSPA1A/HSPA1B protein-protein interactions CTNNB1 HSPB8 phosphorylation CTNNB1 HSPD1 protein-protein interactions CTNNB1 LGALS3 protein-protein interactions CTNNB1 PKM activation CTNNB1 PKM protein-protein interactions CTNNB1 HSPA1A/HSPA1B protein-protein interactions EIF4A3 ENO1 expression ENO1 ENO1 protein-protein interactions ENO1 HNRNPU protein-DNA interactions GAPDH SOD1 protein-protein interactions GAPDH HNRNPD protein-protein interactions HNRNPD HNRNPD protein-RNA interactions HNRNPD KHSRP protein-RNA interactions HNRNPD SFPQ protein-protein interactions HNRNPU HSPA1A/HSPA1B protein-protein interactions HSP90AA1 ITGB1 protein-protein interactions ITGAV CTNNB1 expression ITGB1 CTNNB1 protein-protein interactions ITGB1 ITGAV protein-protein interactions ITGB1 ITGB1 activation ITGB1 LGALS3 protein-protein interactions ITGB1 RAB21 protein-protein interactions ITGB1 SLC3A2 protein-protein interactions ITGB1 VCAM1 activation ITGB1 VCAM1 protein-protein interactions ITGB1 CTNNB1 expression LGALS3 CTNNB1 protein-protein interactions LGALS3 LGALS3 protein-protein interactions LGALS3 SLC3A2 protein-protein interactions LGALS3 MYH9 protein-protein interactions MYH9 S100A4 protein-protein interactions MYH9 NME1 protein-protein interactions NME1 NME2 protein-protein interactions NME1 CTNNB1 expression OAT RPL18A protein-protein interactions PA2G4 PKM protein-protein interactions PKM YWHAE protein-protein interactions PRDX6 CTNNB1 expression RAB18 S100A4 protein-protein interactions S100A4 SOD1 protein-protein interactions SOD1 SQSTM1 protein-protein interactions SOD1 SPTBN1 protein-protein interactions SPTAN1 CTNNB1 protein-DNA interactions SQSTM1 SQSTM1 protein-protein interactions SQSTM1 TARDBP expression SQSTM1 TARDBP expression TARDBP TARDBP transcription TARDBP YWHAE protein-protein interactions TOP2A CTNNB1 expression VCAM1 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Supplementary file 4F: MaxQuant Parameters

Parameter Value Version 1.6.1.0 Fixed modifications Carbamidomethyl (C) Include contaminants True PSM FDR 0.01 XPSM FDR 0.01 Protein FDR 0.01 Site FDR 0.01 Use Normalized Ratios For Occupancy True Min. peptide Length 7 Min. score for unmodified peptides 0 Min. score for modified peptides 40 Min. delta score for unmodified peptides 0 Min. delta score for modified peptides 6 Min. unique peptides 0 Min. razor peptides 1 Min. peptides 1 Use only unmodified peptides and True Modifications included in protein quantification Oxidation (M);Acetyl (Protein N-term) Peptides used for protein quantification Razor Discard unmodified counterpart peptides True Label min. ratio count 2 Use delta score False iBAQ True iBAQ log fit True Match between runs True Matching time window [min] 1 Alignment time window [min] 20 Find dependent peptides False Fasta file Database - Homo sapiens; Date - 02 May 2018; Annotated proteins - 20341 Fasta file Database - Mus musculus; Date - 02 May 2018; Annotated proteins - 16970 Decoy mode revert Include contaminants True Advanced ratios True Fixed andromeda index folder Temporary folder Combined folder location Second peptides True Stabilize large LFQ ratios True Separate LFQ in parameter groups True Require MS/MS for LFQ comparisons True Calculate peak properties False Main search max. combinations 200 Advanced site intensities True LFQ norm for sites and peptides False Write msScans table True Write msmsScans table True Write ms3Scans table True Write allPeptides table True Write mzRange table True Write pasefMsmsScans table True Write accumulatedPasefMsmsScans table True Max. peptide mass [Da] 4600 Min. peptide length for unspecific search 8 Max. peptide length for unspecific search 25 Razor protein FDR True Disable MD5 False Max mods in site table 3 Match unidentified features False MS/MS tol. (FTMS) 20 ppm Top MS/MS peaks per Da interval. (FTMS) 12 Da interval. (FTMS) 100 MS/MS deisotoping (FTMS) True MS/MS deisotoping tolerance (FTMS) 7 MS/MS deisotoping tolerance unit (FTMS) ppm MS/MS higher charges (FTMS) True MS/MS water loss (FTMS) True MS/MS ammonia loss (FTMS) True MS/MS dependent losses (FTMS) True MS/MS recalibration (FTMS) False MS/MS tol. (ITMS) 0.5 Da Top MS/MS peaks per Da interval. (ITMS) 8 Da interval. (ITMS) 100 MS/MS deisotoping (ITMS) False MS/MS deisotoping tolerance (ITMS) 0.15 MS/MS deisotoping tolerance unit (ITMS) Da MS/MS higher charges (ITMS) True MS/MS water loss (ITMS) True MS/MS ammonia loss (ITMS) True MS/MS dependent losses (ITMS) True MS/MS recalibration (ITMS) False MS/MS tol. (TOF) 40 ppm Top MS/MS peaks per Da interval. (TOF) 10 Da interval. (TOF) 100 MS/MS deisotoping (TOF) True MS/MS deisotoping tolerance (TOF) 0.01 MS/MS deisotoping tolerance unit (TOF) Da MS/MS higher charges (TOF) True MS/MS water loss (TOF) True MS/MS ammonia loss (TOF) True MS/MS dependent losses (TOF) True MS/MS recalibration (TOF) False MS/MS tol. (Unknown) 0.5 Da Top MS/MS peaks per Da interval. (Unknown) 8 Da interval. (Unknown) 100 MS/MS deisotoping (Unknown) False MS/MS deisotoping tolerance (Unknown) 0.15 MS/MS deisotoping tolerance unit (Unknown) Da MS/MS higher charges (Unknown) True MS/MS water loss (Unknown) True MS/MS ammonia loss (Unknown) True MS/MS dependent losses (Unknown) True MS/MS recalibration (Unknown) False Site tables Oxidation (M)Sites.txt bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Supplementary File S3 proteomics method

Protein extraction

Protein extraction from the cell culture samples was carried out employing T-PER Tissue

Protein Extraction Reagent (Thermo Scientific Inc., Waltham, MA, USA) according to an in-house

established method catered especially for small amounts of samples, as described elsewhere [1].

Three biological replicates were utilized for each cell culture sample for this proteomics analysis.

Briefly, 400 µl T-PER reagent was added to 70 µl samples from each replicate. Next, the samples

were subjected to homogenization employing zirconium oxide beads in a bullet blender

homogenizer (Bullet Blender Storm BBY24M, Next Advance Inc., Averill Park, NY, USA).

Homogenates were centrifuged at 10,000 × g for 5 minutes to pellet tissue debris and, the

supernatant was subjected to sample cleaning and buffer exchange employing the Amicon Ultra-

0.5 centrifugal filter devices with 3K cutoff (Merck Millipore, Carrigtwohill, Ireland). Sample protein

concentration of the obtained concentrate was determined using the standard bicinchoninic acid

(BCA) Protein Assay Kit (Pierce, Rockford, IL) according to the manufacturer’s instruction.

Sample preparation and 1-dimensional gel electrophoresis (1DE)

The samples were then subjected to 1DE (50 μg per well) employing precast NuPAGE 4-

12% Bis-Tris 10-well mini protein gels (Invitrogen, Karlsruhe, Germany) with 2-[N-

morpholino]ethanesulfonic acid (MES) running buffer under reducing conditions at a constant

voltage of 150V in 4 °C. Pre-stained protein standard, SeeBlue Plus 2 (Invitrogen, Karlsruhe,

Germany) was used as a molecular mass marker and the gels were stained with Colloidal Blue

Staining Kit (Invitrogen, Karlsruhe, Germany), as per manufacturer’s instructions. Protein bands

were excised (20 bands per replicate), reduced and alkylated prior to in-gel trypsin digestion

employing sequence grade-modified trypsin (Promega, Madison, USA), as described in detail

elsewhere [1]. Peptides extracted from trypsin digestion were purified using SOLAµ SPE HRP

plates (Thermo Fisher Scientific, Rockford, USA) according to the manufacturer’s instructions.

1 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

The resulting combined peptide eluate was concentrated to dryness in a centrifugal vacuum

evaporator and dissolved in 10 μl of 0.1% trifluoroacetic acid (TFA) for LC-MS/MS analysis.

Discovery proteomics strategy

Peptide fractionation was conducted in the liquid chromatography (LC) system, which

consisted of a Rheos Allegro pump (Thermo Scientific, Rockford, USA) and an HTS PAL

autosampler (CTC Analytics AG, Zwingen, Switzerland) equipped with a BioBasic C18, 30 x 0.5

mm precolumn (Thermo Scientific, Rockford, USA) connected to a BioBasic C18, 150 x 0.5 mm

analytical column (Thermo Scientific, Rockford, USA). Solvent A consisted of LC-MS grade water

with 0.1 % (v/v) formic acid and solvent B was LC-MS grade acetonitrile with 0.1 % (v/v) formic

acid. The gradient was run for 60 min per sample as follows: 0-35 min: 15-40 % B, 35-40 min: 40-

60 % B, 40-45 min: 60-90 % B, 45-50 min: 90 % B, 50-53 min: 90-10 % B: 53-60 min: 10 % B.

The continuum MS data were obtained on an ESI-LTQ Orbitrap XL-MS system (Thermo Scientific,

Bremen, Germany). The general parameters of the instrument were set as follows: positive ion

electrospray ionization mode, a spray voltage of 2.15 KV and a heated capillary temperature of

220 ºC. Data was acquired in an automatic dependent mode whereby, there was automatic

acquisition switching between Orbitrap-MS and LTQ MS/MS. The Orbitrap resolution was 30000

at m/z 400 with survey full scan MS spectra ranging from an m/z of 300 to 1600. Target automatic

gain control was set at 1.0 x 106 ion. Internal recalibration employed polydimethlycyclosiloxane

(PCM) at m/z 445.120025 ions in real time and the lock mass option was enabled in MS mode

[2]. Tandem data was obtained by selecting top five most intense precursor ions and subjected

them for further fragmentation by collision-induced dissociation. The normalized collision energy

was set to 35 % with activation time of 30 ms with repeat count of 3 and dynamic exclusion

duration of 600 s. The resulting fragmented ions were recorded in the LTQ. The acquired

continuum MS spectra were analyzed by MaxQuant computational proteomics platform version

1.6.1.0 and its built-in Andromeda search engine for peptide and protein identification [3], [4], [5],

[6], [7]. A target-decoy-based false discovery rate (FDR) for peptide and protein identification was

2 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

set to 0.01. The summary of MaxQuant parameters employed in the current analyses is tabulated

in Supplementary file S4F “Proteomics data”.

Bioinformatics and functional annotation and pathways analyses

The output of the generated data from the MaxQuant analysis was utilized for subsequent

statistical analysis with Perseus software (version 1.6.1.0). First, a log2 transformation of all LFQ

intensities was done and the degree of variances in the proteome between the biological

replicates and groups were assessed by Pearson's correlation analysis [7] .Next, the data were

filtered with minimum of three valid values in at least one group and the missing values were

replaced from normal distribution (width, 0.3; down shift, 1.8) using the standard settings in

Perseus. For statistical evaluation a Student’s two-sided t-test was used for the groups’

comparison with Permutation-based FDR ˂ 0.05 to identify the significantly differentially abundant

proteins. Unsupervised hierarchical clustering analysis of the differentially expressed proteins

was conducted with the z-scores of the LFQ intensities according to Euclidean distance (linkage

= average; preprocess with k-means) and elucidated in a heat map. The list of the identified

proteins was tabulated in Excel and their gene names were used for subsequent functional

annotation and pathways analyses employing Ingenuity Pathway Analysis (v01-04, IPA; Ingenuity

QIAGEN Redwood City, CA) (https://www.qiagenbioinformatics.com/products/ingenuity-

pathway-analysis) [8]. IPA analyses elucidated the Gene Ontology Cellular Component (GOCC)

terms, molecular types, protein-protein interaction (PPI) networks, and top disease functions

associated with the proteins identified to be differentially expressed. Top canonical pathways of

the differentially expressed proteins were presented with p-value calculated using Benjamini-

Hochberg (B-H) multiple testing correction (–log B-H > 1.3). In PPI networks, proteins molecules

are represented by their corresponding gene names and, only PPIs that were experimentally

observed and had direct interactions were used.

3 bioRxiv preprint doi: https://doi.org/10.1101/580977; this version posted March 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

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