Bacterial Hsp90 Mediates the Degradation of Aggregation-Prone Hsp70-Hsp40 Substrates Preferentially by Hsluv Proteolysis
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A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
At Elevated Temperatures, Heat Shock Protein Genes Show Altered Ratios Of
EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 900, 2021 At elevated temperatures, heat shock protein genes show altered ratios of different RNAs and expression of new RNAs, including several novel HSPB1 mRNAs encoding HSP27 protein isoforms XIA GAO1,2, KEYIN ZHANG1,2, HAIYAN ZHOU3, LUCAS ZELLMER4, CHENGFU YUAN5, HAI HUANG6 and DEZHONG JOSHUA LIAO2,6 1Department of Pathology, Guizhou Medical University Hospital; 2Key Lab of Endemic and Ethnic Diseases of The Ministry of Education of China in Guizhou Medical University; 3Clinical Research Center, Guizhou Medical University Hospital, Guiyang, Guizhou 550004, P.R. China; 4Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; 5Department of Biochemistry, China Three Gorges University, Yichang, Hubei 443002; 6Center for Clinical Laboratories, Guizhou Medical University Hospital, Guiyang, Guizhou 550004, P.R. China Received December 16, 2020; Accepted May 10, 2021 DOI: 10.3892/etm.2021.10332 Abstract. Heat shock proteins (HSP) serve as chaperones genes may engender multiple protein isoforms. These results to maintain the physiological conformation and function of collectively suggested that, besides increasing their expres‑ numerous cellular proteins when the ambient temperature is sion, certain HSP and associated genes also use alternative increased. To determine how accurate the general assumption transcription start sites to produce multiple RNA transcripts that HSP gene expression is increased in febrile situations is, and use alternative splicing of a transcript to produce multiple the RNA levels of the HSF1 (heat shock transcription factor 1) mature RNAs, as important mechanisms for responding to an gene and certain HSP genes were determined in three cell increased ambient temperature in vitro. lines cultured at 37˚C or 39˚C for three days. -
1 Supplemental Appendix Table of Contents Author
Supplemental Appendix Table of Contents Author Lists………………………………………………….…..2-3 Supplemental Figures …………………………………..……..4-20 Supplemental Tables …………………………………….…….21-41 Supplemental References……………………………………..42 ! 1! Brittany A. Goods, PhD1,2*, Michael H. Askenase, PhD3*, Erica Markarian4, Hannah E. Beatty3, Riley Drake1, Ira Fleming1, Jonathan H. DeLong3, Naomi H. Philip5, Charles C. Matouk, MD6, Issam A. Awad, MD7, Mario Zuccarello, MD8, Daniel F. Hanley, MD9, J. Christopher Love, PhD2,4,10,#, Alex K. Shalek, PhD1,2,4,11,12,13,14,#, and Lauren H. Sansing, MD, MS3,15,#, on behalf of the ICHseq Investigators 1Department of Chemistry and Institute for Medical Engineering & Science, Massachusetts Institute of Technology 2Broad Institute, Harvard University & Massachusetts Institute of Technology 3Department of Neurology, Yale University School of Medicine 4Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology 5Department of Immunobiology, Yale University School of Medicine 6Department of Neurosurgery, Yale University School of Medicine 7Department of Neurosurgery, University of Chicago 8Department of Neurosurgery, University of Cincinnati 9Brain Injury Outcomes Division, Johns Hopkins School of Medicine 10Department of Chemical Engineering, Massachusetts Institute of Technology 11Ragon Institute, Harvard University, Massachusetts Institute of Technology, & Massachusetts General Hospital 12Division of Health Science & Technology, Harvard Medical School 13Program in Computational & Systems Biology, Massachusetts -
1714 Gene Comprehensive Cancer Panel Enriched for Clinically Actionable Genes with Additional Biologically Relevant Genes 400-500X Average Coverage on Tumor
xO GENE PANEL 1714 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes 400-500x average coverage on tumor Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11 IL6R KAT5 ACVR2A -
Functional and Physical Interaction Between Yeast Hsp90 and Hsp70
Functional and physical interaction between yeast PNAS PLUS Hsp90 and Hsp70 Andrea N. Kravatsa, Joel R. Hoskinsa, Michael Reidyb, Jill L. Johnsonc, Shannon M. Doylea, Olivier Genesta,1, Daniel C. Masisonb, and Sue Wicknera,2 aLaboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; bLaboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and cDepartment of Biological Sciences, University of Idaho, Moscow, ID 83844 Contributed by Sue Wickner, January 25, 2018 (sent for review November 17, 2017; reviewed by Daniel N. A. Bolon and Jeffrey L. Brodsky) Heat shock protein 90 (Hsp90) is a highly conserved ATP-dependent changes in response to ATP binding, hydrolysis, and ADP release molecular chaperone that is essential in eukaryotes. It is required for (1,3,6,14–16). In the absence of ATP, the Hsp90 dimer acquires the activation and stabilization of more than 200 client proteins, an open, V-shaped structure such that the protomers interact via including many kinases and steroid hormone receptors involved in the C-terminal dimerization domain (16). When ATP is bound, the cell-signaling pathways. Hsp90 chaperone activity requires collabo- protein takes on a closed conformation with the two N-domains of ration with a subset of the many Hsp90 cochaperones, including the the dimer interacting and a portion of the N-domain, the “lid,” Hsp70 chaperone. In higher eukaryotes, the collaboration between closing over the nucleotide in each protomer (16, 17). Additional Hsp90 and Hsp70 is indirect and involves Hop, a cochaperone that conformational changes occur upon ATP hydrolysis, resulting in a interacts with both Hsp90 and Hsp70. -
(HECT) E3 Ubiquitin Ligase Family. NEDD3 Is Overexpressed in CRC Patients, and NEDD4 Promotes Colon Cancer Cell Growth [1, 2]
Supplementary Materials NEDD3 belongs to the homologous to E6AP C-terminus (HECT) E3 ubiquitin ligase family. NEDD3 is overexpressed in CRC patients, and NEDD4 promotes colon cancer cell growth [1, 2]. The expression levels of the signal transducer and activator of transcription 1 and 3 (STAT1 and STAT3) were investigated in CRC biopsy samples of 400 patients [3]. The results suggested that STAT1 and STAT3 are effective prognostic biomarkers in CRC. In addition, activation of STAT3 promotes rectal cancer growth by inducing loss of PTPN4 [4]. TRAF6 is a member of the tumor-necrosis factor family and is involved in the NF-kappa B signaling pathway. Wu et al. showed that TRAF6 can effectively suppress CRC metastasis by promoting CTNNB1 degradation, suggesting its potential as a target for the treatment of advanced CRC [5]. HSP90AA1 and HSP90AB1 belong to the heat shock protein 90 family. Drug resistance caused by HSP90AA1-mediated autophagy was observed in chemotherapy-treated osteosarcoma [6]. Wang et al. suggested that HSP90AB1 could serve as a novel biomarker of poor prognosis in lung adenocarcinoma. The association of these genes with CRC remains to be established [7]. Table S1. Differentially expressed genes between responders and non-responders in the training cohort. Sr. No. Gene p-value Fold-Change * 1 ID1 2.17 × 10−2 −2.78 2 WNT11 1.99 × 10−2 −2.32 3 NKD1 1.90 × 10−3 −2.27 4 SFN 2.45 × 10−3 −2.24 5 LAMA5 8.51 × 10−3 −1.96 6 CACNA1D 5.06 × 10−4 −1.96 7 IKBKB 9.91 × 10−3 −1.88 8 PLA2G4F 5.89 × 10−3 −1.83 9 CDK6 3.63 × 10−3 −1.79 10 CIC 1.21 × 10−2 −1.76 11 SMARCB1 5.80 × 10−4 −1.75 12 SRSF2 3.07 × 10−3 −1.73 13 IKBKG 1.51 × 10−2 −1.68 14 BAP1 9.01 × 10−3 −1.68 15 SPRY2 1.52 × 10−3 −1.65 16 AXIN2 5.01 × 10−3 −1.65 17 GNA11 6.73 × 10−3 −1.64 18 FGFR4 1.69 × 10−3 −1.64 19 FGFR3 1.05 × 10−3 −1.62 20 HDAC10 1.08 × 10−3 −1.62 21 SGK2 5.64 × 10−3 −1.6 22 H3F3A 2.42 × 10−3 −1.58 23 EPHA2 1.74 × 10−2 −1.57 24 U2AF1 4.56 × 10−3 −1.56 25 ITGB4 3.14 × 10−3 −1.56 26 TRAF7 6.07 × 10−3 −1.54 27 CBL 5.56 × 10−3 −1.53 28 MAP2K2 1.99 × 10−3 −1.51 Sr. -
The HSP70 Chaperone Machinery: J Proteins As Drivers of Functional Specificity
REVIEWS The HSP70 chaperone machinery: J proteins as drivers of functional specificity Harm H. Kampinga* and Elizabeth A. Craig‡ Abstract | Heat shock 70 kDa proteins (HSP70s) are ubiquitous molecular chaperones that function in a myriad of biological processes, modulating polypeptide folding, degradation and translocation across membranes, and protein–protein interactions. This multitude of roles is not easily reconciled with the universality of the activity of HSP70s in ATP-dependent client protein-binding and release cycles. Much of the functional diversity of the HSP70s is driven by a diverse class of cofactors: J proteins. Often, multiple J proteins function with a single HSP70. Some target HSP70 activity to clients at precise locations in cells and others bind client proteins directly, thereby delivering specific clients to HSP70 and directly determining their fate. In their native cellular environment, polypeptides are participates in such diverse cellular functions. Their constantly at risk of attaining conformations that pre- functional diversity is remarkable considering that vent them from functioning properly and/or cause them within and across species, HSP70s have high sequence to aggregate into large, potentially cytotoxic complexes. identity. They share a single biochemical activity: an Molecular chaperones guide the conformation of proteins ATP-dependent client-binding and release cycle com- throughout their lifetime, preventing their aggregation bined with client protein recognition, which is typi- by protecting interactive surfaces against non-productive cally rather promiscuous. This apparent conundrum interactions. Through such inter actions, molecular chap- is resolved by the fact that HSP70s do not work alone, erones aid in the folding of nascent proteins as they are but rather as ‘HSP70 machines’, collaborating with synthesized by ribosomes, drive protein transport across and being regulated by several cofactors. -
Supplementary Material Contents
Supplementary Material Contents Immune modulating proteins identified from exosomal samples.....................................................................2 Figure S1: Overlap between exosomal and soluble proteomes.................................................................................... 4 Bacterial strains:..............................................................................................................................................4 Figure S2: Variability between subjects of effects of exosomes on BL21-lux growth.................................................... 5 Figure S3: Early effects of exosomes on growth of BL21 E. coli .................................................................................... 5 Figure S4: Exosomal Lysis............................................................................................................................................ 6 Figure S5: Effect of pH on exosomal action.................................................................................................................. 7 Figure S6: Effect of exosomes on growth of UPEC (pH = 6.5) suspended in exosome-depleted urine supernatant ....... 8 Effective exosomal concentration....................................................................................................................8 Figure S7: Sample constitution for luminometry experiments..................................................................................... 8 Figure S8: Determining effective concentration ......................................................................................................... -
HSP90-Incorporating Chaperome Networks As Biosensor for Disease-Related Pathways in Patient- Specific Midbrain Dopamine Neurons
ARTICLE DOI: 10.1038/s41467-018-06486-6 OPEN HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient- specific midbrain dopamine neurons Sarah Kishinevsky1,2,3,4, Tai Wang3, Anna Rodina3, Sun Young Chung1,2, Chao Xu3, John Philip5, Tony Taldone3, Suhasini Joshi3, Mary L. Alpaugh3,14, Alexander Bolaender3, Simon Gutbier6, Davinder Sandhu7, Faranak Fattahi1,2, Bastian Zimmer1,2, Smit K. Shah3, Elizabeth Chang5, Carmen Inda3,15, John Koren 3rd3,16, Nathalie G. Saurat1,2, Marcel Leist 6, Steven S. Gross7, Venkatraman E. Seshan8, Christine Klein9, Mark J. Tomishima1,2,10, Hediye Erdjument-Bromage11,12, Thomas A. Neubert 11,12, Ronald C. Henrickson5, 1234567890():,; Gabriela Chiosis3,13 & Lorenz Studer1,2 Environmental and genetic risk factors contribute to Parkinson’s Disease (PD) pathogenesis and the associated midbrain dopamine (mDA) neuron loss. Here, we identify early PD pathogenic events by developing methodology that utilizes recent innovations in human pluripotent stem cells (hPSC) and chemical sensors of HSP90-incorporating chaperome networks. We show that events triggered by PD-related genetic or toxic stimuli alter the neuronal proteome, thereby altering the stress-specific chaperome networks, which produce changes detected by chemical sensors. Through this method we identify STAT3 and NF-κB signaling activation as examples of genetic stress, and phospho-tyrosine hydroxylase (TH) activation as an example of toxic stress-induced pathways in PD neurons. Importantly, pharmacological inhibition of the stress chaperome network reversed abnormal phospho- STAT3 signaling and phospho-TH-related dopamine levels and rescued PD neuron viability. The use of chemical sensors of chaperome networks on hPSC-derived lineages may present a general strategy to identify molecular events associated with neurodegenerative diseases. -
And Chemically Upregulated Chaperone Genes in Plant and Human Cells
Cell Stress and Chaperones (2011) 16:15–31 DOI 10.1007/s12192-010-0216-8 ORIGINAL PAPER Meta-analysis of heat- and chemically upregulated chaperone genes in plant and human cells Andrija Finka & Rayees U. H. Mattoo & Pierre Goloubinoff Received: 18 June 2010 /Revised: 16 July 2010 /Accepted: 19 July 2010 /Published online: 9 August 2010 # Cell Stress Society International 2010 Abstract Molecular chaperones are central to cellular protein Keywords Chaperone network . Heat shock proteins . homeostasis. In mammals, protein misfolding diseases and Foldase . NSAID . Cellular stress response . aging cause inflammation and progressive tissue loss, in Unfolded protein response correlation with the accumulation of toxic protein aggregates and the defective expression of chaperone genes. Bacteria and non-diseased, non-aged eukaryotic cells effectively respond Introduction to heat shock by inducing the accumulation of heat-shock proteins (HSPs), many of which molecular chaperones The term “heat-shock proteins” (HSPs) was first used to involved in protein homeostasis, in reducing stress damages describe Drosophila melanogaster proteins that and promoting cellular recovery and thermotolerance. We massively accumulate during heat stress (Tissieres et al. performed a meta-analysis of published microarray data and 1974). When subject to a sharp increase in temperature, compared expression profiles of HSP genes from mammalian prokaryotes and eukaryotes alike transiently reallocate and plant cells in response to heat or isothermal treatments their general house-keeping protein synthesis machinery with drugs. The differences and overlaps between HSP and to the specific accumulation of a small subset of highly chaperone genes were analyzed, and expression patterns were conserved Hsps, initially named according to their clustered and organized in a network. -
Prognostic and Functional Significant of Heat Shock Proteins (Hsps)
biology Article Prognostic and Functional Significant of Heat Shock Proteins (HSPs) in Breast Cancer Unveiled by Multi-Omics Approaches Miriam Buttacavoli 1,†, Gianluca Di Cara 1,†, Cesare D’Amico 1, Fabiana Geraci 1 , Ida Pucci-Minafra 2, Salvatore Feo 1 and Patrizia Cancemi 1,2,* 1 Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy; [email protected] (M.B.); [email protected] (G.D.C.); [email protected] (C.D.); [email protected] (F.G.); [email protected] (S.F.) 2 Experimental Center of Onco Biology (COBS), 90145 Palermo, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-091-2389-7330 † These authors contributed equally to this work. Simple Summary: In this study, we investigated the expression pattern and prognostic significance of the heat shock proteins (HSPs) family members in breast cancer (BC) by using several bioinfor- matics tools and proteomics investigations. Our results demonstrated that, collectively, HSPs were deregulated in BC, acting as both oncogene and onco-suppressor genes. In particular, two different HSP-clusters were significantly associated with a poor or good prognosis. Interestingly, the HSPs deregulation impacted gene expression and miRNAs regulation that, in turn, affected important bio- logical pathways involved in cell cycle, DNA replication, and receptors-mediated signaling. Finally, the proteomic identification of several HSPs members and isoforms revealed much more complexity Citation: Buttacavoli, M.; Di Cara, of HSPs roles in BC and showed that their expression is quite variable among patients. In conclusion, G.; D’Amico, C.; Geraci, F.; we elaborated two panels of HSPs that could be further explored as potential biomarkers for BC Pucci-Minafra, I.; Feo, S.; Cancemi, P. -
Characterization of the Dual Functional Effects of Heat Shock Proteins (Hsps
Zhang et al. Genome Medicine (2020) 12:101 https://doi.org/10.1186/s13073-020-00795-6 RESEARCH Open Access Characterization of the dual functional effects of heat shock proteins (HSPs) in cancer hallmarks to aid development of HSP inhibitors Zhao Zhang1†, Ji Jing2†, Youqiong Ye1, Zhiao Chen1, Ying Jing1, Shengli Li1, Wei Hong1, Hang Ruan1, Yaoming Liu1, Qingsong Hu3, Jun Wang4, Wenbo Li1, Chunru Lin3, Lixia Diao5*, Yubin Zhou2* and Leng Han1* Abstract Background: Heat shock proteins (HSPs), a representative family of chaperone genes, play crucial roles in malignant progression and are pursued as attractive anti-cancer therapeutic targets. Despite tremendous efforts to develop anti-cancer drugs based on HSPs, no HSP inhibitors have thus far reached the milestone of FDA approval. There remains an unmet need to further understand the functional roles of HSPs in cancer. Methods: We constructed the network for HSPs across ~ 10,000 tumor samples from The Cancer Genome Atlas (TCGA) and ~ 10,000 normal samples from Genotype-Tissue Expression (GTEx), and compared the network disruption between tumor and normal samples. We then examined the associations between HSPs and cancer hallmarks and validated these associations from multiple independent high-throughput functional screens, including Project Achilles and DRIVE. Finally, we experimentally characterized the dual function effects of HSPs in tumor proliferation and metastasis. Results: We comprehensively analyzed the HSP expression landscape across multiple human cancers and revealed a global disruption of the co-expression network for HSPs. Through analyzing HSP expression alteration and its association with tumor proliferation and metastasis, we revealed dual functional effects of HSPs, in that they can simultaneously influence proliferation and metastasis in opposite directions.