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Functions and mechanisms of non-

Narita, Takeo; Weinert, Brian T; Choudhary, Chunaram

Published in: Nature Reviews. Molecular Cell Biology

DOI: 10.1038/s41580-018-0081-3

Publication date: 2019

Document version Peer reviewed version

Citation for published version (APA): Narita, T., Weinert, B. T., & Choudhary, C. (2019). Functions and mechanisms of non-histone protein acetylation. Nature Reviews. Molecular Cell Biology, 20, 156-174. https://doi.org/10.1038/s41580-018-0081-3

Download date: 26. sep.. 2021 Functions and mechanisms of non-histone protein acetylation

Takeo Narita, Brian T. Weinert, Chunaram Choudhary*

The Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark

*Correspondence should be addressed to: CC, [email protected]

Abstract | N-ε- acetylation was discovered more than half a century ago as a posttranslational modification of and has been extensively studied in the context of regulation. In the past decade, proteomic analyses have revealed that non-histone are frequently acetylated and constitute a major portion of the acetylome in mammalian cells. Indeed, non-histone protein acetylation is involved in key cellular processes relevant to physiology and disease, such as transcription, DNA damage repair, cell division, signal transduction, , autophagy and metabolism. Acetylation affects protein functions through diverse mechanisms, including by regulating protein stability, enzymatic activity, subcellular localization, cross-talk with other posttranslational modifications, and by controlling protein–protein and protein–DNA interactions. In this Review, we discuss recent progress in our understanding of the scope, functional diversity and mechanisms of non-histone protein acetylation.

Introduction

Precise control of protein function is essential for the organization and function of biological systems. Among different regulatory processes, reversible posttranslational modifications (PTMs) provide an elegant mechanism to govern protein function. A key advantage of PTMs is that they can be dynamically regulated at a much faster rate and with a lower energy cost compared with protein turnover. Eukaryotic proteomes contain hundreds of different types of PTMs; however, only a small number of them, such as , , , acetylation, ubiquitylation, and sumoylation have been studied extensively.

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Although the physiological importance of PTMs has been known for more than half a century, the widespread occurrence of PTMs only started to become clear in the first years of the 21st century, when advances in high-resolution mass spectrometry enabled detection of thousands of low- abundance PTM sites1. It is also increasingly appreciated that combinations of PTMs can generate distinct protein isoforms with varying functions, which vastly expand the functional diversity of mammalian proteomes2.

Lysine acetylation is an evolutionarily conserved PTM, occurring in both prokaryotes and eukaryotes. Acetylation was first discovered on histones by Vincent Allfrey and colleagues in 19643. Subsequently, acetylation was found on high mobility group (HMG) proteins4, which are chromatin-binding non-histone proteins, and on tubulin5. In the mid to late 1990s, acetylation of the was discovered, the first mammalian histone acetyltransferases (HATs) and histone deacetylases (HDACs) were identified, the bromodomain was identified as an acetyl-lysine reader domain, and potent deacetylase inhibitors were discovered (reviewed in6). These groundbreaking discoveries set the stage for the field of non-histone protein acetylation. We wish to clarify that the term ‘acetylation’ can encompass other types of protein acetylation, such as N-terminal protein acetylation and O-linked acetylation of and . Unless otherwise specified, in this Review ‘acetylation’ refers only to N-ε-lysine acetylation.

Over the past decade, advances in mass-spectrometry-based proteomics have vastly expanded the catalogue of endogenously acetylated proteins, provided an unbiased view of the acetylome, and revealed new insights into the scope and regulation of non-histone protein acetylation. In appreciation of the extent of non-histone acetylation, HATs and HDACs were renamed to lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), respectively. The identification of thousands of acetylation sites has spurred great interest in wide range of biomedical research communities, and non-histone protein acetylation has been implicated in all major biological processes (see below).

In this review, we provide an overview of the expanding landscape of non-histone protein acetylation. We discuss the subcellular, compartment-specific generation of the acetyl-group

2 donor acetyl-CoA, enzymatic regulation of acetylation, and the emerging non-enzymatic mechanisms of acetylation. The major focus is on acetylation, however, related lysine acylations are also briefly discussed. Although it is challenging to comprehensively review this rapidly growing field, we discuss a plethora of functionally characterized acetylation sites on non-histone proteins to illustrate the functional diversity and mechanistic principles of acetylation. We also briefly describe the disease and therapeutic relevance of acetylation, and conclude with discussing key open questions and future perspectives. Because histone acylation was extensively covered in a recent review7, it will not be covered here.

The scope of non-histone acetylation Until the beginning of the 21st century, acetylation was mostly identified on individual proteins using conventional approaches, such as in vitro acetyltransferase assays with radioisotope labeled acetyl-CoA or using acetyl-lysine antibodies. In 2006, a combination of acetylated peptide immunoaffinity-enrichment and high-resolution mass spectrometry enabled the identification of hundreds of acetylation sites8. Subsequently, the identification of thousands of acetylation sites from human cell lines was reported9. These unbiased proteomic analyses showed that acetylation was a surprisingly common modification of proteins in diverse cellular compartments. Many ensuing studies firmly established that, in addition to histones, acetylation occurs on tens of thousands of non-histone proteins in evolutionarily diverse organisms10. In recent years mass- spectrometry-based studies have quantified the relative changes at thousands of acetylation sites in response to genetic, chemical, and metabolic perturbations, and provided insights into the dynamic regulation of lysine acetylation11-15.

Regulation of acetylation Acetylation is generated by KAT-catalyzed transfer of an acetyl group from acetyl-CoA to the - amino side chain of lysine, and is reversed by KDACs (Fig. 1a). Recent studies show that acetylation also occurs through non-enzymatic mechanisms and is affected by the availability of acetyl-CoA (BOX 1).

Regulation of acetyl-CoA synthesis

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Acetyl-CoA is a key metabolite with essential cellular functions, such as energy generation in the mitochondria and biosynthesis of lipids in the . Because acetyl-CoA is membrane- impermeable, mitochondrial and non-mitochondrial pools of acetyl-CoA are generated independently (Fig. 1b). Depending on the nutrient source, mitochondrial acetyl-CoA is generated by the pyruvate dehydrogenase complex (PDC), by beta-oxidation of fatty acids, or through metabolism. The non-mitochondrial pool of acetyl-CoA is generated in the cytoplasm and nucleus by ATP-citrate lyase (ACLY; also known as ATP-citrate synthase) and acyl-CoA synthetase short-chain family member 2 (ACSS2), as well as by the nuclear PDC. Acetyl-CoA can freely diffuse between the cytoplasm and nucleus through the nuclear pores.

Acetylation is directly linked to acetyl-CoA levels, and cell-compartment-specific generation of acetyl-CoA can locally fuel acetylation. For example, nuclear ACLY, ACSS2 and PDC are reported to regulate histone acetylation and gene transcription through localized production of acetyl-CoA16. In yeast, depletion of mitochondrial acetyl-CoA only ablates acetylation of mitochondrial proteins, without affecting acetylation of nuclear proteins17. In mice, of both acetyl-CoA carboxylase 1 (ACC1) and ACC2, which convert cytoplasmic acetyl-CoA to malonyl-CoA (Fig. 1b), results in increased protein acetylation18, likely through an increase in the levels of acetyl-CoA. Fluctuations in acetyl-CoA levels by genetic and dietary manipulations correlate with changes in acetylation levels, further indicating that acetyl-CoA is a rate-limiting factor for many acetylation events (reviewed in13).

Lysine acetyltransferases The exact number of bona fide KATs in the human proteome is unclear. Among the reported KATs, thirteen are well-characterized (‘canonical’) and a majority of them are classified into three families: GCN5, p300 and MYST19 (Fig. 1c). The remaining KATs: alpha-tubulin N-acetyltransferase 1 (ATAT1; also known as TAT1), ESCO1 and ESCO2, and histone acetyltransferase 1 (HAT1), are relatively dissimilar to each other. With the exception of TAT1, all of the canonical KATs are primarily localized in the nucleus and acetylate histones and non-histone proteins. Compared with protein kinases, much less is known about the substrate specificities of KATs. The substrate specificity of KATs is thought to be defined by their specific subcellular localization, interacting proteins, and the accessibility of lysine in substrate proteins. Many KATs acetylate non-redundant

4 substrates, but some of the closely related KATs can acetylate the same sites and show functional redundancy; for example, CREB-binding protein (CBP; also known as KAT3A) and p300 (also known as KAT3B) acetylate histone H3 Lys18 (H3K18) and H3K2720, GCN5 (also known as KAT2A) and P300/CBP-associated factor (PCAF; also known as KAT2B) acetylates H3K920, KAT6A and KAT6B acetylate H3K2321 and ESCO1 and ESCO2 acetylate structural maintenance of protein 3 (SMC3) Lys105 and Lys10622, 23.

In addition to the canonical KATs, a growing number of proteins have been reported to function as non-canonical KATs19. However, we do not discuss non-canonical KATs here because very little is known about their substrate specificity and enzymatic mechanisms. We think that a more rigorous demonstration of their KAT activities is necessary before they can be classified as genuine KATs. For example, ARD1, which is the catalytic subunit of the N-terminal acetyltransferase A complex, is implicated in lysine acetylation of several non-histone proteins (Supplementary Table 1), but its lysine acetyltransferase activity has been questioned24. The deletion of another reported KAT, ACAT125, had no measurable impact on the acetylome of HCT116 cells (B.T.W., C.C. unpublished results). Furthermore, acetylation of almost all sites on several reported KATs; nuclear coactivator 1 (NCOA1), NCOA2, and NCOA314, is reduced upon inhibition of CBP and p30026, indicating that they are possibly targets of CBP and/or p300 instead.

Lysine deacetylases The encodes 18 KDACs, which can be grouped into two major categories: Zn2+- dependent HDACs and NAD+-dependent sirtuin deacetylases (Fig. 1d). The Zn2+-dependent HDACs share a highly conserved deacetylase domain and often referred to as classical HDACs or classical KDACs. Based on their phylogenetic conservation and sequence similarities, the classical KDACs are further divided into four classes: class I, class IIa, class IIb and class IV27, 28 (Fig. 1d). Class I and IV KDACs are nuclear, class IIb KDACs are cytoplasmic, and the signal-responsive class IIa KDACs are primarily nuclear, but are exported to the cytoplasm upon activation of signaling. Sirtuin deacetylases, which are also referred to as class III KDACs, localize to different cellular compartments, including the nucleus (SIRT1, SIRT6), nucleolus (SIRT7), cytoplasm (SIRT2) and mitochondria (SIRT3, SIRT4 and SIRT5)29.

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Notably, nearly half of the ‘deacetylases’ have weak or no deacetylase activity, or target other types of acylations. For example, SIRT5 functions as dessucinylase, demalonylase and deglutarylase30-32; SIRT4 removes the acyl moieties from methylglutaryl-lysine, hydroxymethylglutaryl-lysine and 3-methylglutaconyl-lysine33; SIRT6 functions as a long-chain -acylase34; and class IIa KDACs lack appreciable catalytic activity owing to a change of a conserved amino acid in the catalytic pocket27.

Histone deacetylase activity was recently reported for the transcription factors T-cell-specific transcription factor 1 (TCF1) and lymphoid enhancer-binding factor 1 (LEF1), which function in the WNT signaling pathway35. TCF1 and LEF1 have similarity to HDAC8, and of conserved residues in the reported catalytic domain abolished their deacetylase activity. However, the overall sequence similarity between TCF1, LEF1 and HDAC8 is very weak and additional work is required to confirm their deacetylase activity.

Functional acetylation networks To obtain an overview of the functional diversity of non-histone protein acetylation, we curated a list of ~550 studies covering ~380 functionally characterized non-histone proteins, mostly from mammals (Supplementary Table 1). Where available, we also retrieved information about the sites of acetylation, the responsible KATs and KDACs, and the functional consequences of acetylation. Because acetylation of some of proteins, such as p53 and tubulin, is extensively studied, this partial list only includes key publications related to the initial identification of acetylation sites and their regulatory enzymes.

Using these literature-curated data we built networks of functionally characterized proteins as well as their links to KATs and KDACs (Supplementary Figure 1, Supplementary Figure 2). A notable conclusion that can be drawn from these networks is that a disproportionately large number of functionally-investigated acetylation is linked to a few well-characterized KATs and KDACs. Another interesting observation is that proteins involved in transcription regulation are greatly overrepresented in these networks and constitutes >40% of functionally characterized KAT substrates. This is consistent with the nuclear localization of most canonical KATs.

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Over two-thirds of acetylation sites with known KATs are targets of CBP and/or p300, and ~90% of acetylated proteins are catalyzed by just five KATs (CBP, p300, GCN5, PCAF and TIP60) (Supplementary Figure 1). The number of functionally characterized, acetylated non-histone proteins linked to CBP and/or p300 is considerably larger than the number of CBP and/or p300 substrates identified by unbiased acetylome analysis14. The overrepresentation of CBP and p300 in these networks is likely due to several factors: firstly, due to their key function in transcription regulation there is likely a bias in investigating their substrates; second, CBP and p300 have robust acetyltransferase activities in vitro and upon overexpression in cells, making it easier to identify their targets; and third, CBP-regulated and/or p300-regulated acetylation sites have higher than average stoichiometry14, which likely contributed to their easier detection by immunoblotting and mass spectrometry. CBP and p300 are each linked to a larger number of unique targets than the number of targets they share (Supplementary Figure 1). However, many studies investigating the involvement of CBP and p300 in substrate acetylation tested only one of these enzymes and it is likely that CBP and p300 commonly acetylate a much larger group of proteins than depicted in Supplementary Figure 1. Notably, only a few or no functionally characterized non-histone substrates are reported for the MYST family acetyltransferases, with the exception of TIP60. Finally, there are few or no non-histone substrates known for the poorly characterized non- canonical KATs (Supplementary Table 1).

Similar to the KAT-regulated networks, a disproportionately large number of substrates are linked to a few KDACs, mostly to sirtuins. Over 40% of acetylation sites are targets of SIRT1, and more than two-thirds of sites are targets of sirtuin deacetylases in general (Supplementary figure 2). In agreement with the distinct cellular localization of sirtuins, SIRT1 targets include many nuclear proteins such as transcription regulators, whereas most SIRT3 targets are involved in regulating metabolism in mitochondria (Supplementary Table 1). A possible explanation for the overrepresentation of sirtuins compared to classical HDACs is that the chemical inhibitors used for studying classical HDACs, such as trichostatin A, inhibit the activity of multiple KDACs. Thus, in these studies it is not possible to attribute the deacetylase activity to a specific enzyme(s), and the KDACs targeting these sites are not specified. In comparison to the KAT-regulated networks, KDAC- regulated networks encompass fewer transcription regulators, but include a larger fraction of proteins involved in metabolism, which are mostly targeted by SIRT2 and SIRT3.

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It should be pointed out that a vast majority of functionally characterized acetylation enzyme– substrate relationships were discovered by hypothesis-driven research and are likely to be biased for extensively studied proteins. Regardless, collectively these studies provide a snapshot of the broad regulatory landscape of lysine acetylation.

Cellular roles of acetylation Acetylation of non-histone proteins is implicated in diverse cellular processes and human diseases. As such, acetylation-regulating enzymes and acetyl-lysine reader domain containing proteins are attractive therapeutic targets (BOX 2).

Gene transcription Protein acetylation is a major regulator of gene transcription. Most of the canonical KATs localize to the nucleus and function as transcription co-activators. Similarly, almost all acetyl-lysine- binding, bromodomain-containing proteins are localized to the nucleus and many of them are directly involved in transcription regulation. The tumor suppressor p53 was the first transcription factor identified to undergo acetylation36. Acetylation of p53 regulates its DNA binding, stability, and interaction with other proteins, and strongly correlates with activation of p53-regulated in response to cellular stress37. Overall, acetylation is implicated in regulating over one hundred non-histone transcription-regulating proteins, including transcription factors, transcriptional co- activators and nuclear receptors (Supplementary Table 1). Thus, regulation of gene transcription is a major role of non-histone protein acetylation.

Cell cycle During DNA replication, sister chromatids are paired together by the cohesion complex until their separation in mitosis. The ATPase head of SMC3, which is a key component of the cohesion complex, is acetylated at two conserved DNA-sensing residues, Lys105 and Lys10638-40.Once SMC3 is loaded onto DNA, acetylation of SMC3 ‘locks’ the cohesion ring, thereby establishing stable sister chromatid cohesion (Fig. 2a). In mammalian cells, SMC3 is acetylated by ESCO1 and to a lesser extent by ESCO215. Combined depletion of ESCO1 and ESCO2 cause severe defects in chromatid cohesion and the cells are inviable22. Interestingly, the cohesion complex may be

8 released in the acetylated form during prophase and anaphase, and HDAC8-dependent deacetylation is required for dissolution of the released complex41. This implies that, although acetylation of SMC3 stabilizes chromatid cohesion, SMC3 can be released from the chromatin by a deacetylation-independent mechanism. Recent work suggests that acetylation of SMC3 is also important for non-cohesive functions of SMC3, for example in gene transcription and DNA damage repair22, 23. Indeed, chromatin loading of the hyper-acetylated form of cohesin resulted in altered gene transcription in HDAC8 mutant cells derived from individuals with Cornelia de Lange syndrome41. Acetylation also modulates several other major regulators, including the protein kinases BUBR1, Aurora kinase A, Aurora kinase B , cyclin-dependent kinase 1 (CDK1), CDK2, and PLK4 (Supplementary Table 1). Acetylation-dependent regulation of diverse cell-cycle regulating protein kinases raises an interesting possibility that cell-cycle regulation is coordinated in concert by acetylation and phosphorylation. However, further work is required to understand KAT and KDAC activities during the cell cycle and the possible interplay between acetylation and phosphorylation during the cell cycle.

DNA damage repair The kinase ataxia telangiectasia mutated (ATM) is a key regulator of DNA double-strand break (DSB) repair. TIP60 acetylates and activates ATM in response to DNA damage, and inactivation of TIP60 sensitizes cells to ionizing radiation42 (Fig. 2b). Furthermore, acetylation regulates DSB- repair pathway choice between non-homologous end-joining (NHEJ) and homology-directed repair (HDR), by regulating the recruitment of the NHEJ-promoting factor TP53-binding protein 1 (53BP1) to DNA damage sites. TIP60-catalyzed acetylation of histone H4 prevents binding of the Tudor domain of 53BP1 to dimethylated H4K20 (H4K20me2)43, and TIP60-catalyzed acetylation of H2AK15 prevents ubiquitylation of this residue (H2AK15ub) and thus inhibits 53BP1 recruitment to H2AK15Ub through its ubiquitylation-dependent recruitment (UDR) domain44. DNA damage- induced phosphorylation of ACLY by ATM enhances nuclear production of acetyl-CoA, resulting in enhanced histone acetylation and impaired chromatin localization of 53BP145. Direct acetylation of 53BP1 by CBP also interferes with 53BP1 recruitment to damaged chromatin46 (Fig. 2b). Thus, acetylation of 53BP1 and histones interferes with the 53BP1 recruitment and promotes HDR over NHEJ.

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Acetylation also regulates proteins involved in the base excision repair (BER) and nucleotide excision repair (NER) pathways. DNA damage-induced acetylation of APE1 (apurinic/apyrimidinic endonuclease 1), which is an essential component of BER, inhibits its interaction with XRCC1 and reduces APE1 activity; SIRT1-catalyzed deacetylation restores APE1 function47. Acetylation also inhibits the catalytic activity and DNA binding of the BER (and replication) factor flap endonuclease 148.

Functions of the NER factor XPA (DNA repair protein complementing XP-A cells) and of replication factor A protein 1 (RPA1) are inversely regulated by acetylation. XPA is deacetylated by SIRT1 following ultraviolet irradiation, and this promotes its interaction with RPA and chromatin49. By contrast, RPA1 is acetylated following ultraviolet irradiation to increase its retention on chromatin50. Proliferating cell nuclear antigen (PCNA) is also acetylated following ultraviolet- induced DNA damage. After completion of NER, acetylated PCNA is removed from chromatin and degraded by the proteasome51. Thus, acetylation-dependent removal of PCNA prevents its excessive retention on chromatin, which otherwise could compromise genome stability. Collectively, acetylation of histone and non-histone proteins appears to regulate repair of various types of DNA lesions.

Cellular signaling CBP-mediated acetylation of the PH domain of connector enhancer of kinase suppressor of ras 1 (CNK1) drives its localization to the plasma membrane, where it interacts with the serine/threonine kinase RAF to phosphorylate and stimulate ERK-dependent cell proliferation and migration52 (Fig. 2c). Activation of ERK signaling forms a feedback loop that reinforces CNK1 acetylation. SIRT1-catalyzed deacetylation of receptor substrate 2 (IRS2), which is a key adaptor of insulin and insulin-like growth factor 1 (IGF1) signaling, enhances its phosphorylation and activation of ERK signaling53. SIRT1 inhibition increases IRS2 acetylation and inhibits IGF1 signaling, possibly by promoting IRS2 .

The levels of the plasma membrane-associated signaling messenger phosphatidylinositol (3,4,5)- trisphosphate (PIP3) are regulated by the kinase PI(3)K and the phosphatase PTEN. PCAF acetylates PTEN within its catalytic domain and thereby inhibits it54. By contrast, acetylation of PTEN at its

10 carboxy-terminus by CBP promotes its interaction with PDZ domain containing proteins such as membrane-associated guanylate kinase inverted-2 (MAGI2)55, which enhances the lipid phosphatase activity of PTEN and recruits it to signaling complexes at the membrane56 (Fig. 2c). Acetylation of the kinases AKT and PDK1 in their PH domains by PCAF and p300 prevents their

57 PIP3-dependent membrane localization and activation . By contrast, deacetylation by SIRT1 enhances their PIP3 binding and promotes their kinase activity.

Acetylation of the mTORC2 subunit rapamycin-insensitive companion of mTOR (RICTOR) by p300 increases mTORC2-mediated phosphorylation of AKT (Fig. 2c). Likewise, inhibition of sirtuin deacetylases enhances RICTOR acetylation and IGF1-induced phosphorylation of AKT58. Acetylation of RICTOR is enhanced by supply of or acetate59, possibly through enhanced synthesis of acetyl-CoA. In conditions of elevated glucose, RICTOR acetylation supports sustained mTORC2 activation even in the absence of upstream signaling by growth factor receptors. Because AKT kinases are key drivers of cell proliferation and survival, acetylation-dependent activation of mTORC2–AKT likely promotes these processes.

Protein folding -assisted protein folding is fundamentally important for attaining a functionally mature protein state. Heat shock proteins (HSPs), which comprise a major class of eukaryotic chaperones, are targeted by acetylation, including HSP10, , and HSPA5 (Supplementary Table 1). Acetylation of HSP90 impairs its association with an essential co-chaperone, p23, resulting in the loss of chaperone activity60. HSP90 is deacetylated by HDAC6, and genetic deletion or pharmacological inhibition of HDAC6 compromises maturation of the , which is an HSP90 client60. HSP90 is important for the folding of many signaling-relevant proteins, and its inhibition synergizes with KDAC inhibitors in impeding the proliferation of cells expressing oncogenic kinases61, 62.

Cytoskeleton organization Microtubules, which are formed by polymerization of -tubulin and -tubulin, are a major component of the cytoskeleton in eukaryotic cells. Alpha-tubulin is acetylated at Lys40 by the cytoplasmic acetyltransferase TAT163, and deacetylated by the cytoplasmic deacetylase HDAC664,

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65 (Fig. 3a). TAT1 was proposed to enter microtubules through microtubule ends or through breathing (stretching) of the microtubule sidewall, and uses a highly unusual mechanism to acetylate -tubulin within the microtubule lumen66, 67. Deletion of TAT1 causes migratory defects in cortical projection neurons and interneurons; depletion of HDAC6 or overexpression of an acetylation mimetic α-tubulin (K40Q) reduces the TAT1-deficiency phenotype68, indicating that tubulin is a key target of TAT1. TAT1 depletion increases the frequency of mechanical-stress- induced microtubule breakage, indicating that acetylation increases the mechanical resilience of microtubules to ensure the persistence of long-lived microtubules67. In T cells, tubulin acetylation regulates immune synapse organization and antigen-specific reorientation of the microtubule organizing center69.

Acetylation also regulates another major cytoplasmic protein, Cortactin, which binds to F-actin and contributes to organization of actin cytoskeleton and cell migration (Fig. 3b). Cortactin is acetylated by CBP andp30070, 71. Acetylated cortactin is mostly localized in the nucleus71. Acetylation decreases binding of cortactin to KEAP1 and inhibits cell migration71, whereas HDAC6, SIRT2 and SIRT1-dependent deacetylation promotes cell motility70, 72.

Protein aggregation Accumulation of protein aggregates is associated with various neurological pathologies. Several aggregation-prone proteins are acetylated, including Huntingtin, tau, superoxide dismutase 1 (also known as superoxide dismutase [Cu-Zn]) and TDP43, and this affects their aggregation. Acetylation of TDP43, which is implicated in amyotrophic lateral sclerosis, impairs its RNA binding and promotes accumulation of an insoluble, hyper-phosphorylated form of TDP4373 (Fig. 3c). The acetylation-mimetic mutant TDP43 K145Q promotes TDP43 phosphorylation, ubiquitylation, and aggregation74.

The microtubule-binding protein tau is acetylated at multiple residues by CBP and p30075, 76, and through its own autocatalytic activity77. Acetylation of tau within its microtubule-binding motif impairs tau–microtubule interactions and promotes pathological tau aggregation75, 78 (Fig. 3d). Tau acetylation at Lys174 is an early marker of Alzheimer´s disease. Inhibition of p300 reduces tau acetylation, enhances tau turnover, ameliorates tau-induced memory deficits, and prevent

12 neuronal damage76. Acetylation of tau at Lys259 and Lys353 in KXGS motifs inhibits phosphorylation of proximal Ser262 and Ser356, and thereby prevents the formation of hyperphosphorylated tau aggregates79 (Fig. 3d). Inhibition of HDAC6 increases tau acetylation, reduces tau phosphorylation and promotes tau clearance79. These studies indicate that distinct acetylation sites could differentially impact tau aggregation.

RNA processing and stability Acetylation regulates various steps of posttranscriptional RNA processing, including pre-mRNA splicing and polyadenylation, and polyadenylated mRNA degradation (mRNA decay). Acetylation of CFIm25, which is a component of the cleavage factor Im (CFIm) complex, and of the polyadenylation enzyme poly(A) polymerase (PAP) suppresses mRNA polyadenylation through two mecahnisms80 (Fig. 3e). First, CFIm25 and PAP directly interact with each other, and acetylation by CBP at their interacting regions inhibits their association. Second, acetylation of PAP causes its export to the cytoplasm. Furthermore, CBP and p300 promote mRNA decay by acetylating and activating CCR4-associated factor 1 (CAF1; also known as CCR4–NOT transcription complex subunit 7), which is a catalytic subunit of the CCR4–NOT1 deadenylase complex81. During differentiation, expression of CBP and p300 is reduced, resulting in increased stabilization of polyadenylated mRNA. By contrast, inhibition of HDAC1 and HDAC2 induces widespread mRNA decay in mammalian and Drosophila melanogaster cells, possibly through elevated protein acetylation.

Autophagy The acetyltransferases CBP, p300, and TIP60, and the deacetylases HDAC6 and SIRT1, are important regulators of autophagy. Depending on the target protein, acetylation can enhance or inhibit autophagy. For example, nutrient starvation induces the activation of glycogen synthase kinase-3, which phosphorylates and activates TIP60 (Fig. 4). TIP60 acetylates and stimulates the kinase ULK1, which is required for autophagy82.

The activity of CBP and p300 is regulated by mTORC1. In nutrient-rich conditions, mTORC1 phosphorylates p300 at carboxy-terminal serine residues, thereby alleviating its auto-inhibition, suppressing autophagy and promoting lipogenesis instead83. p300 acetylates the key autophagy

13 factors autophagy protein 5 (ATG5), ATG7, microtubule-associated protein light chain 3 (LC3; ATG8 in yeast) and ATG12, , thereby inhibiting autophay84 (Fig. 4). UVRAG complex, composed of VPS34- VPS15-Beclin 1-UVRAG, plays an important role in the maturation of autophagosomes by promoting autophagosome-lysosome fusion; and interaction with Rubicon inhibits the function of UVRAG complex85. Acetylation of VPS34, a class III phosphatidylinositol-3 kinase, hinders binding to its substrate phosphatidylinositol and inhibits VPS34-Beclin 1 interaction86. Acetylation of Beclin 1 promotes recruitment of Rubicon to the UVRAG complex and thereby inhibits the maturation of autophagosomes87. SIRT1 interacts with and directly deacetylates ATG5, ATG7 and ATG8, and its catalytic activity is required for autophagy88. In particular, LC3 shuttles between the nucleus and cytoplasm, and during nutrient starvation it is selectively deacetylated by SIRT189 (Fig. 4). Deacetylated LC3 interacts with diabetes- and obesity-regulated gene (DOR) and translocates to the cytoplasm, where it interacts with ATG7 to promote autophagy. Increased SIRT1 expression enhances basal autophagy, and SIRT1-deficient mouse embryonic fibroblasts fail to fully activate autophagy88.

HDAC6 is the only mammalian deacetylase that contains a -binding domain and proficiently interacts with ubiquitylated proteins. Consequently, HDAC6 has a key role in autophagy-dependent protein degradation when the ubiquitin proteasome system is impaired90. HDAC6 also facilitates microtubule-dependent transport of protein aggregates and damaged mitochondria to autophagosomes and promotes lysosome-autophagosome fusion through deacetylating cortactin, which contributes to the formation of F-actin networks91, 92 (Fig. 4). The emerging picture shows that acetylation regulates diverse proteins that intersect at various steps of autophagy. In the future it would be interesting to investigate whether the acetylation of different autophagy-regulators is coordinated.

Other regulatory functions In addition to the major biological processes discussed above, non-histone protein acetylation is implicated in a growing number of other processes, including acetylation of proteins involved in DNA replication (TOPBP1, MCM10), (Ku70, p53), lipid storage and breakdown (CAVIN1, CIDEC), mitochondrial fission and fusion (MFN1, MFN2, OPA1), protein synthesis (eIF2A, eIF5A), ion transport (AMPAR, KCNA5, KCNAB2) and redox regulation (PRX1, PRX2; Supplementary Table

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1). Acetylation is also extensively involved in regulation of metabolism; we refer the reader to several excellent recent reviews on this topic13, 29, 93.

Functional mechanisms of acetylation Positively charged lysine residues frequently participate in protein–protein interactions and in protein catalytic activities. Acetylation neutralizes the positive charge of lysine and thus affects diverse aspects of protein function, such as stability, enzymatic activity, subcellular localization and interaction with other macromolecules in the cell.

Regulation of enzymes Through diverse mechanisms, acetylation regulates the activities of more than 40 enzymes, which localize to various cellular compartments (Supplementary table 1).

Inhibition of catalytic activity Acetylation inactivates the enzymatic activities of the acetyl-CoA synthetases 1 (AceCS1) and AceCS294, 95, which localizes to the cytoplasm and mitochondria, respectively. Deacetylation of AceCS1 and AceCS2, by SIRT1 and SIRT3, respectively, restores their catalytic function (Fig. 5a). KAT9-catalyzed acetylation of glucose-6-phosphate dehydrogenase (G6PD) inhibits the formation of active G6PD dimers, resulting in loss of enzymatic activity96 (Fig. 5a). SIRT2-catalyzed deacetylation restores G6PD function and protects cells from oxidative damage. Acetylation inhibits many mitochondrial enzymes93, and sirtuin deacylases restore their catalytic activity97, 98. For example, acetylation inhibits the catalytic activity of long-chain acyl coenzyme A dehydrogenase, which is restored by deacetylation by SIRT399.

In addition to metabolic enzymes, acetylation impairs the catalytic activities of many other enzymes. For example, the cell-cycle regulating kinases CDK1, CDK2, and CDK5 are acetylated at a conserved lysine that is directly involved in ATP binding; consequently, acetylation prevents ATP binding and inhibits kinase activity9, 100.

Enhancement of catalytic activity

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Autoacetylation enhances the activity of several KATs, including p300, PCAF, and MOF (KAT8)101. Autoacetylation of p300 within its activation loop motif, relieves autoinhibition and activates the enzyme102 (Fig. 5b). This mechanism is reminiscent protein kinases activation via autophosphorylation at their activation loop regions. Stimulation of macrophages by lipopolysaccharides causes p300-mediated acetylation of MAPK phosphatase 1 (MKP1) within its substrate-binding domain103. Acetylation increases the phosphatase activity of MKP1 and enhances its interaction with the MAPK p38, thereby inhibiting MAPK signaling. Conversely acetylation of p38 itself, in its ATP-binding pocket, increases the affinity of p38 for ATP and enhances its kinase activity104.

Alteration of enzyme–substrate specificity Acetylation can switch the substrate specificity of E3 ubiquitin–protein ligase from autoubiquitylation to ubiquitylating its major substrate p53. MDM2 acetylation at Lys182 and Lys185 by p300 enables its binding to the deubiquitylase USP7, which shifts the ubiquitylation activity of MDM2 towards p53 ubiquitylation, thereby also increasing the stability of MDM2105 (Fig. 5c). Upon genotoxic stress, SIRT1 deacetylates MDM2, thereby promoting its self- ubiquitylation and degradation; this reduces p53 ubiquitylation, increases p53 stability and promotes apoptosis.

Regulation of protein degradation Lysine acetylation can regulate both proteasome-dependent and proteasome-independent protein degradation.

Ubiquitylation and proteasome-dependent degradation A common mechanism of acetylation-dependent protein stability is prevention of protein ubiquitylation and thereby inhibition of proteasome-dependent degradation (Supplementary Table 1). This could be due to direct competition between acetylation and ubiquitylation for modification of the same lysine residues. For example, p300-mediated acetylation of SMAD7 at Lys64 and Lys70 prevents their ubiquitylation by SMAD ubiquitylation regulatory factor 1 (SMURF1), thereby preventing degradation of SMAD7106 (Fig. 5d). Acetylation can also promote protein degradation by enhancing ubiquitylation. PEPCK1 acetylation recruits E3 ubiquitin-protein

16 ligase UBR5, resulting in PEPCK1 ubiquitylation and degradation107. Similarly, acetylation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) promotes its ubiquitylation by E3 ubiquitin–protein ligase UHRF1, thereby targeting DNMT1 for proteasomal degradation108 (Fig. 5d). Acetylation and deacetylation of DNMT1 are regulated by TIP60 and HDAC1, respectively.

Proteasome-independent degradation Acetylation also regulates protein stability through ubiquitin–proteasome-independent mechanisms. Acetylation of pyruvate kinase PKM targets it for degradation through chaperone- mediated autophagy109. Likewise, acetylation of lactate dehydrogenase A at Lys5 inhibits its activity, promotes its recognition by the chaperone heat shock cognate 71 kDa protein (also known as HSPA8) and targets it to lysosomes for degradation110.

Protein–protein interactions Acetylation of non-histone proteins can promote or inhibit protein–protein interactions.

Promoting protein–protein interactions Acetylation-dependent protein interactions are studied most extensively in the context of the bromodomain, which interacts with acetylated proteins. The human proteome includes 61 unique bromodomains within 46 proteins, almost all of which are nuclear111. Bromodomain-acetyl-lysine interactions are best characterized for the bromodomain and extra-terminal (BET) protein family, which includes bromodomain-containing protein 2 (BRD2), BRD3, BRD4, and bromodomain testis- specific protein (BRDT). BET proteins interact with acetylated histone tails and regulate . Acetylation of HIV-1 protein Tat abrogates its interaction with HIV-1 trans-activation response (TAR) RNA; instead, Tat acetylation enhances its interaction with the bromodomain of PCAF and the transcriptional activity of Tat. Thus, the bromodomain of PCAF competes with TAR RNA for Tat binding112.

The bromodomain interaction is characterized by low affinity and by ligand promiscuity113, which could provide high responsiveness and binding to a wide range of ligands. The affinity of protein interactions can be enhanced also by binding tandem bromodomains and by to multiply acetylated proteins. For example, acetylation of the transcription factor C-ets-1 (ETS1)

17 at two residues in its amino-terminus promotes its interaction with BRD4 and the release of RNA polymerase II that is paused at promoters of target genes of vascular endothelial growth factor114. Similarly, acetylation of the transcription regulator Twist-related protein 1 (twist) promotes its interaction with the second bromodomain of BRD4, while the first bromodomain of BRD4 interacts with acetylated histone H4, thereby promoting the formation of a complex comprising twist, BRD4, Pol II and the positive transcription elongation factor b (P-TEFb) complex at the and enhancer of the gene encoding Wnt-5A115 (Fig. 5e). Bromodomains can also function in combination with other PTM-binding domains to increase the affinity and specificity of protein interactions. Phosphorylation of cyclic AMP-responsive element-binding protein (CREB) promotes its interaction with the KIX domain of CBP, whereas acetylation of CREB promotes its interaction with the bromodomain of CBP, resulting in reciprocal modification-dependent binding that is thought to augment the recruitment of CBP to gene promoters116.

Inhibiting protein–protein interactions NF-κB inhibitor (IB ) interacts with and retains NF-B p65 subunit in the cytoplasm, thereby inhibiting its transcriptional activity. Acetylation of p65 impairs its interaction with IB  whereas p65 deacetylation by HDAC3 promotes its nuclear export and degradation117. Acetylation of lysine residues in the carboxy-terminal domain (CTD) of p53 disrupts its interactions with several proteins harboring acidic domains, including the proteins; SET, VPRBP, DAXX, and PELP1118. The acidic domains serve as ‘converse readers’, which interact with positively charged, non-acetylated lysine residues in the p53 CTD, and their acetylation disrupts these interactions.

Regulation of DNA binding The transcription factor 1 (HSF1) is a key regulator of genes involved in protein folding. Acetylation of HSF1 inhibits its binding to the HSP70 promoter, and deacetylation by SIRT1 restores its DNA–binding capacity119. Acetylation of the CTD of p53 enhances its interaction with its cognate DNA sequences120, and TIP60-catalyzed acetylation of p53 within its DNA binding domain enhances its recruitment to promoters of pro-apoptotic genes121, 122. Similarly, acetylation of the transcription factor GATA1 increases its interaction with DNA123.

Regulation of subcellular localization

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Acetylation controls the localization of dozens of non-histone proteins (Supplementary Table 1).

Enhancement of cytoplasmic localization Acetylation by p300 of S-phase kinase-associated protein 2 (SKP2) at its nuclear localization signal (NLS) promotes its cytoplasmic retention and inhibits its degradation124. Depletion of the deacetylase SIRT3 increases SKP2 retention in the cytoplasm, where it enhances cell migration through ubiquitylation and degradation of E-cadherin. Similarly, viral infection triggers p300- dependent acetylation of the NLS of the viral-DNA sensor gamma-interferon-inducible protein 16 (IFI16), thereby promoting its cytoplasmic localization125 (Fig. 5f). Through an alternative mechanism, acetylation of transcription factor promotes its association with the nuclear export machinery, causing its re-localization into the cytoplasm and subsequent degradation by the ubiquitin–proteasome pathway126.

Enhancement of nuclear localization CBP-catalyzed acetylation of the NLS of hepatocyte nuclear factor 4 (HNF4) promotes its nuclear retention127. Non-acetylated HNF4 is exported to the cytoplasm trough the exportin 1 pathway. Acetylation of the transcription regulator CtBP2 is also required for its nuclear retention128.

Extracellular secretion High mobility group protein B1 (HMGB1) is primarily a chromatin-binding protein. However, upon monocyte and macrophage activation, these cells secrete HMGB1 to induce . This process is regulated by HMGB1 acetylation, which triggers its relocalization to the , concentration into secretory lysosomes, and subsequent extracellular secretion129.

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the conversion of nicotinamide into NAD+. Mammalian cells express two different NAMPT isoforms, intra-cellular and extra-cellular NAMPT (iNAMPT and eNAMPT, respectively). SIRT1-catalyzed deacetylation of NAMPT enhances its activity and triggers its secretion from ; the secreted eNAMPT promotes NAD+ biosynthesis, sirtuin activation, and neural activity in the hypothalamus130.

Membrane localization

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The SIRT1 deacetylase regulates the acetylation and membrane localization of the cardiac-specific voltage-gated sodium channel subunit alpha Nav1.5 (also known as SCN5A)131. Cardiac-specific SIRT1 deficiency leads to Nav1.5 hyperacetylation and decreased levels of Nav1.5 on the cardiomyocyte cell membrane, resulting in cardiac conduction abnormalities and premature death. By contrast, acetylation of Ras–MAPK signaling regulator CNK1 within its PH domain drives its localization to the cell membrane52.

Translocation to mitochondria In conditions of high glucose, acetylation of the signaling adaptor 66-kDa Src homology 2 domain- containing protein (p66Shc) promotes its phosphorylation at Ser36 and translocation to the mitochondria, where it increases the production of reactive oxygen species through the generation of hydrogen peroxide132. SIRT1 deacetylases p66Shc Lys81, and knock-in mice expressing a non-acetylatable form of the protein are protected from .

Cross-talk with other PTMs Most mammalian proteins are modified by multiple PTMs, which can reciprocally influence each other; this is often referred to as ‘PTM crosstalk.’ PTM crosstalk can integrate diverse signals and vastly increase their regulatory potential. Because the amino group of lysine can be diversely modified, including by acetylation and other acylations, methylation, ubiquitylation, and ubiquitin- like modifiers, this can result in ‘competitive’ PTM crosstalk whereby different PTMs compete for modifying the same lysine residue133. Proteomic studies reveal that a large fraction of acetylated lysine residues are also targeted by other PTMs, such as ubiquitylation and succinylation134, 135. However, the mere occurrence of different PTMs on the same lysine does not indicate ‘competitive’ crosstalk. Although a proteome-wide analysis of crosstalk between acetylation and other PTMs has not been performed, here we discuss specific examples of acetylation crosstalk. Because transcription factors and other transcription regulators are among the most extensively studied group of acetylated non-histone proteins, it is not surprising that this group of proteins is frequently reported to harbor acetylation crosstalk with other PTMs.

20 p53 is an archetypical example of PTM crosstalk at non-histone proteins37. Acetylation of p53 at its CTD lysine residues directly competes with MDM2-catalyzed ubiquitylation of the same residues, thereby inhibiting ubiquitin–proteasome-dependent degradation136 (Fig. 6a). Reciprocally, MDM2 inhibits CBP-catalyzed and p300-catalyzed acetylation of p53137. Acetylation of p53 can be enhanced by histone-lysine N-methyltransferase SETD7 (SET7/9)-catalyzed methylation, which promotes recruitment of TIP60 and thereby enhances acetylation at p53 Lys120121, 138. Independently of this mechanism, SETD7 negatively regulates SIRT1 and thereby increases acetylation of p53 at Lys382139.

The farnesoid X-activated receptor (FXR; also known as bile acid receptor) is sumoylated by the E3 SUMO ligase PIAS (also known as PIAS4), which results in the interaction of

FXR with NF-B p65 subunit and transcriptional repression of proinflammatory genes (Fig. 6b). Acetylation of FXR at Lys217 blocks its interaction with PIAS and activates proinflammatory genes140.

Several transcription factors, such as HSF1, HIC1, and members of family, are sumoylated in a phosphorylation-dependent manner141-144. In all cases, phosphorylation, at the phosphorylation- dependent SUMO motif ψKX(D/E)XXSP145, promotes sumoylation of the lysine within the motif sequence. Conversely, dephosphorylation results in decreased desumoylation, and increased acetylation of the same lysine. HIC1 and MEF2 are acetylated by CBP and p300 and deacetylated by SIRT1143, 144. MEF2A and MEF2D are phosphorylated and dephosphorylated by CDK5 and Cacineurin142. Phosphorylation-dependent sumoylation of MEF2A inhibits its transcriptional activity and promotes dendritic maturation at neurons and synapse formation146 (Fig. 6c). Calcium signaling promotes dephosphorylation and desumoylation of MEF2A and promotes acetylation, thereby establishing reciprocal regulation of MEF2A activity by sumoylation and acetylation.

Phosphorylation of NF-B p65 subunit at Ser276 and Ser536 by MAPK and IκB kinase (IKK), respectively, promotes its subsequent acetylation by p300 at Lys310 and enhances its transcriptional activity147 (Fig. 6d). When Lys310 is not acetylated and thus is positively charged, it interacts with the methyltransferase SETD7148 (Fig. 6e). Acetylation of p65 at Lys310 prevents

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SETD7 binding and p65 methylation. SIRT1 deacetylates Lys310, thereby enhancing SETD7 recruitment and p65 methylation, which results in proteasome-dependent degradation of p65.

The forkhead box O (FOXO) transcription factors function in different of biological processes, including in metabolism, cell proliferation and stress responses. Phosphorylation of FOXO proteins promotes their interaction with 14-3-3 proteins and their retention in the cytoplasm. In response to extracellular signals, FOXO1 translocates to the nucleus, where it is acetylated and deacetylated by CBP and SIRT2, respectively. Acetylation of FOXO1 at Lys245, Lys248, and Lys265 attenuates its binding to DNA and increases its phosphorylation at Ser256 by AKT149 (Fig. 6f). Phosphorylated FOXO1 is exported from the nucleus and retained in the cytoplasm through its interaction with 14- 3-3.

Open questions and conclusion Impressive progress in the research of non-histone protein acetylation has raised several important questions regarding acetylation mechanisms and differentiating between acetylation and other acylations, to be addressed in future studies.

Acetylation regulation and function Acetylation targets multiple proteins, which function in diverse processes, but it is still relatively little is known about whether acetylation coordinately regulates different proteins involved in specific biological processes, such as cell signaling and apoptosis. This is because most functional studies only investigate acetylation of single proteins. A more integrated analysis of acetylation in specific biological processes could greatly help understand the order in which acetylation targets different proteins in given biological processes and pathways.

For a majority of acetylation sites on non-histone proteins, the responsible enzymes and bromodomain (reader) interactions are unknown. Elucidating enzyme–substrate relationships, distinguishing between enzymatic and non-enzymatic acetylation mechanisms, and identifying ligands of bromodomain proteins, will be important for expanding the functional and mechanistic understandings of acetylation. In this regard, several mass-spectrometry-based studies have revealed a multitude of non-histone proteins targeted by various deacetylases, including SIRT1,

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SIRT2, SIRT3, SIRT6, and HDAC611-13. Furthermore, a global analysis of commonly used KDAC inhibitors has defined their specificities in vivo at thousands of acetylation sites12. Use of genetic knockouts and selective CBP and p300 inhibitors26 has recently provide a comprehensive map of CBP-regulated and/or p300-regulated acetylation sites and their turnover rates14. CBP and p300 acetylate up to one-third of the nuclear acetylome and many of the acetylated proteins show rapid deacetylation kinetics, indicating the existence of a tight equilibrium between the activities of CBP and p300 and of deacetylases. We anticipate many more similar proteomic analyses in the future, which, combined with focused functional analyses, should help decode the acetylome.

The stoichiometry of acetylation A few studies have analyzed proteome-wide stoichiometry of acetylation in eukaryotes, and estimates of acetylation stoichiometry vary substantially when different methods are used for determining stoichiometry. Using an in vitro partial chemical acetylation approach, most of the in yeast17 and murine tissues98 were shown to occur at a low stoichiometry (median 0.02–0.05%). Similarly, the stoichiometry of acetylation remains very low (<1%) in human Hela cells, even when they are treated with aspirin, which causes greatly widespread increased acetylation in cells150. Stoichiometry estimations using fully chemically acetylated peptides were substantially higher151, 152, but these estimates have not been validated independently and further work is required to resolve the question of acetylation stoichiometry.

It should be clarified that low stoichiometry does not indicate lack of functionality. For example, low stoichiometry may be observed if regulation by acetylation is restricted to subset of proteins residing at a specific location and/or occur for a brief period of time in response to a specific perturbation. For example, acetylation of transcription factors may be restricted to gene enhancers and promoters, followed by rapid deacetylation. This could enable tight control over gene expression. Similarly, most studies are conducted using asynchronous cell populations; therefore, cell-cycle-specific acetylation events may appear to occur at a low stoichiometry, even if the targeted protein is fully acetylated at a specific time in the cell cycle. However, stoichiometry is useful in interpreting the implications of acetylation, and mechanistic model should account for the stoichiometry of modification. For example, if acetylation results in inactivation of enzymatic activity, the degree of inactivation should be reflected by the stoichiometry of the modification.

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Distinguishing diverse acylations An increasing number of acylations have been found to target lysine residues, including propionylation, buryrylation, succinylation, crotonylation, and glutarylation7. Identification of their regulatory functions and distinguishing them from acetylation remains a challenge. This task is complicated because many components of the acetylation apparatus, including KATs, KDACs and bromodomain-containing proteins, are also implicated in other (non-acetyl) acylations. For example, p300 can catalyze acetylation, propionylation, butyrlation and cronylation, but the rate of catalysis decreases with increasing length of the acyl-CoA chain153, and crotonylation is catalyzed at a rate that is 50 times slower compared with that of acetylation. Furthermore, some of the canonical acetyl-lysine reader bromodomain-containing proteins can also recognize other lysine acylations, such propionylation, butyrlation, and crotonylation, albeit with varying levels of selectivity154. In addition to the bromodomain, the YEATS domain can interact with crotonylated histone peptides155 and double plant homeodomain (PHD) finger domains interact with diverse acyl-lysine ligands, with their strongest affinity being for crotonylated lysine156. Thus, dedicated readers of other acylations may exist. Defining the relative abundances of various acylations and identifying their regulating enzymes will be crucial for understanding their overlapping and unique regulatory functions.

Conclusion Over the past two decades, we have witnessed tremendous advances in unraveling the scope and understanding the mechanisms and cellular functions of non-histone protein acetylation. The latest advances in high-resolution quantitative mass spectrometry, genome engineering, and development of selective chemical probes provide exciting opportunities for systems-wide investigations and detailed mechanistic studies addressing future challenges.

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Acknowledgements We thank the members of our laboratory for their helpful discussions. We sincerely apologize to our colleagues whose interesting work we were unable to cite owing to space constraints. C.C. is supported by the Hallas Møller Investigator Fellowship from the Novo Nordisk Foundation (NNF14OC0008541). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No

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648039). The Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (Grant agreement: NNF14CC0001).

Author contributions - T.N., B.T.W, and C.C. researching data for the article - B.T.W. and T.N. substantial contributions to the discussion of content - C.C. writing - T.N, B.T.W, C.C reviewing and/or editing the manuscript before submission.

Competing interests The authors declare no competing interests.

Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Main display items, figure legends, and glossary terms BOX 1. Non-enzymatic protein acetylation. An early study showed that histones and synthetic lysine-containing peptides undergo acetylation in vitro in the presence acetyl-CoA157. However, following the discovery of lysine acetyltransferases (KATs), the study of non-enzymatic acetylation in vivo was not pursued. Non- enzymatic acetylation was ‘rediscovered’ only more than four decades later.

The scope of non-enzymatic acetylation in vivo was first appreciated when acetylation was found to be strongly increased in metabolically active but growth-arrested cells17. In yeast, manipulation of acetyl-CoA levels, through genetic and nutritional perturbations, led to corresponding fluctuations in acetylation levels17. Notably, acetylation at nearly all mitochondrial sites was increased uniformly and slowly in growth-arrested cells, suggesting a non-enzymatic mechanism of acetylation. In mice, experimental manipulation of acetyl-CoA levels paralleled changes in acetylation levels, further supporting the existence of non-enzymatic acetylation158, 159. Although

35 the majority of acylation in mitochondria may be caused by a non-enzymatic mechanism, the extent of non-enzymatic acetylation in other cellular compartments is less clear. .

The -amino group of lysine is protonated at acidic and neutral pH. Because lysine must be deprotonated to allow acetylation, the rate of acetylation is influenced by the protonation state of lysine. In enzymatic acetylation, lysine is deprotonated by active-site residues of KATs. However, lysine is naturally deprotonated at alkaline pH, and the deprotonated lysine acts as a nucleophile towards the electrophilic carbonyl center of acetyl-CoA. Thus, alkaline pH increases the proportion of deprotonated , resulting in increased non-enzymatic acetylation157. Indeed, non- enzymatic acetylation preferentially occurs at lysine residues flanked by positively charged amino acids160, and could be favored by the higher pH environment within the mitochondrial matrix161. Acetylation is also influenced by proximal cysteine residues. Through a thiol exchange reaction, acetyl-CoA can cause non-enzymatic cysteine S-acetylation; and via an intramolecular SN-transfer reaction the acetyl group can migrate to the amine group of a neighboring lysine, resulting in lysine acetylation162. Acetylation sites occurring in proximity to cysteine have a substantially higher stoichiometry, supporting the in vivo relevance of this mechanism163 (B.T.W. and C.C. unpublished results).

In addition to acetylation, other acylations can be catalyzed non-enzymatically. Lysine can be acylated by a growing number of acyl-CoAs7, and a non-enzymatic mechanism appears to be relevant to most of them17, 32, 134, 164. Interestingly, some acyl-CoAs, such as succinyl-CoA, glutaryl- CoA, and hydroxymethylglutaryl-CoA are considerably more reactive than acetyl-CoA164. This is because the carboxylate group of these acyl-CoAs can cause an intramolecular nucleophilic attack on the CoA thioester bond, resulting in the formation of a cyclic anhydride that is much more reactive than the parental acyl-CoAs, and can more efficiently modify proteins non-enzymatically.

It is still not fully clear under what conditions non-enzymatic acylation is regulated and what its functions are. Non-enzymatic acylation is affected by the reactivities of acyl-CoAs, the reactivities of different lysine residues in a protein, and by the cellular concentration of acyl-CoAs and local pH, which can vary between different tissues and cellular compartments. . Site-specific acetylation of many metabolic enzymes is reported to affect specific metabolic pathways93 (Supplementary

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Table 1), but there is little understanding of how such site-specific regulation is achieved. Alternatively, but not mutually exclusively, stochastic non-enzymatic acylation may constitute a type of protein damage that accumulates in conditions of acyl-stress or sirtuin (lysine deacetylase) dysfunction. In this model, mitochondrial sirtuins may function as repair factors to remove acyl- lesions and restore proper enzyme function97, 98. In addition to non-enzymatic acetylation, a few studies report that some acetylation sites in mitochondria are enzyme-catalyzed25, 165. The challenge going forward is to develop strategies to identify enzyme-catalyzed acetylation sites and to unravel the functional and regulatory consequences of non-enzymatic acetylation.

BOX 2. Non-histone protein acetylation in disease and as a therapeutic target. Deregulated acetylation is associated with a range of human diseases; thus, proteins involved in acetylation are attractive therapeutic targets. Acetylation deregulation in disease Developmental disorders: Germline mutations in several lysine acetyltransferases (KATs) and deacetylases (KDACs) are involved in disorders associated with developmental delays and abnormalities and intellectual disability. Mutations in CREB-binding protein (CREBBP) and E1A- binding protein p300 (EP300) result in Rubinstein–Taybi syndrome; mutations in KAT6B cause Say- Barber-Biesecker-Young-Simpson syndrome (also known as Ohdo syndrome)166 and Genitopatellar syndrome167, and KAT6A mutations cause intellectual disability and global developmental delay168, 169. A mutation in the gene encoding the KAT6A and KAT6B activator Peregrin (BRPF1) is associated with developmental delays, intellectual impairment and facial dysmorphisms170, 171. Mutations in structural maintenance of chromosomes protein 3 (SMC3) and in its deacetylase HDAC8 are associated with Cornelia de Lange syndrome, whereas mutations in the SMC3 acetyltransferase ESCO2 are associated with . Cancer and other diseases: Acetylation has been linked to cancer since the discovery of acetylation of the tumor suppressor p5336, and since then has been implicated in diverse cancers (for example, somatic mutations in CREBBP and EP300 are frequently detected in leukemia172, 173), inflammation and immunity, and in neurological and metabolic diseases, such as diabetes29, 174. Therapeutic targeting of acetylation Small molecule inhibitors of KDACs, KATs, and bromodomain proteins (BRDs; acetyl-lysine readers) have emerged as attractive therapeutic candidates. Although the biological effects of KDAC, KAT,

37 and bromodomain inhibitors are often linked to histone acetylation, these drugs also regulate non-histone proteins and thus it is likely that non-histone proteins also contribute to their cellular effects. KDAC inhibitors and activators: Extensive efforts in the past two decades have yielded dozens of KDAC inhibitors with varying target specificities174. At least four KDAC inhibitors (vorinostat, romidepsin, panabinostat and belinostat) are clinically approved for treating cutaneous and peripheral T-cell lymphoma as well as , and are being tested for several other cancers. KDAC inhibitors can enhance synaptic plasticity and memory formation in mice175, 176. Indeed, long before the discovery of its KDAC inhibitory activity, valproic acid was used as a mood stabilizer and an anti-epileptic drug. KDAC inhibitors have also been tested for their anti-viral effects; most notably, vorinostat disrupts HIV-1 latency in individuals treated with antiretroviral therapy177. Decreased NAD+ levels and sirtuin function is linked to aging and cancer13, 178; therefore, sirtuin activation may have therapeutic benefits. A number of sirtuin-activating compounds (STACs), such as resveratrol, have been identified179, although the role of sirtuins in ageing and the beneficial effects of STACs are subject of an ongoing debate. Recently, administration of metabolic precursors of NAD+, such as nicotinamide mononucleotide or nicotinamide riboside, has been reported to have various health-beneficial effects180. Although the beneficial effects of NAD+ precursors are often attributed to enhanced sirtuin activation, other functions of NAD+, for example in redox regulation, likely contribute to these effects. KAT inhibitors: The development of KAT inhibitors has lagged behind that of KDAC inhibitors. The recently identified CBP and p300 inhibitor A485 showed anti-proliferative effects on lineage- specific tumor cell lines26. Also, inhibitors of KAT6A and KAT6B induced cellular senescence and inhibited the growth of lymphoma in mice181. In the future, it would be interesting to identify potent and selective inhibitors for other KATs to understand their biological functions and to explore their therapeutic potential. BRD inhibitors: Several small molecule inhibitors have been identified for different bromodomain proteins111, 182. Notably, compounds targeting bromodomain and extra-terminal motif (BET) family of proteins show promising anti-cancer potential and are currently being clinically evaluated.

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Figure legends Fig. 1 | Regulation of reversible lysine acetylation. a | Lysine acetylation occurs through acetyltransferase (KAT)-catalyzed transfer of an acetyl group from acetyl-CoA to the -amino side chain of lysine. Alternatively, acetyl-CoA can acetylate lysine non-enzymatically. Acetylation is reversed by Zn2+-dependent histone deacetylases (HDACs), or by the NAD+-dependent sirtuin family of deacetylases. HDAC-catalyzed deacetylation generates deacetylated lysine and acetate, whereas sirtuin catalyzed deacetylation produces deacetylated lysine, nicotinamide and 2´-O- acetyl-ADP-ribose. b | In mitochondria acetyl-CoA is generated from pyruvate by the pyruvate dehydrogenase complex (PDC), or by the β-oxidation of fatty acids (FA). Mitochondrial acetyl-CoA feeds into the tricarboxylic acid (TCA) cycle. The TCA cycle intermediate citrate can be exported from mitochondria to the cytoplasm, where it freely diffuses into and out of the nucleus. Cytoplasmic and nuclear acetyl-CoA pools are generated by ATP-citrate lyase (ACLY), acetyl-CoA synthetase 2 (ACSS2) and PDC. Cytoplasmic acetyl-CoA can be converted to malonyl-CoA by acetyl-CoA carboxylases 1 (ACC1) and ACC2 and used for synthesis of fatty acids. c | A majority of the canonical mammalian lysine acetyltransferases (KATs) are classified into three major families: GGN5, p300 and MYST. The remaining (‘other’) KATs are relatively dissimilar to each- other. The subcellular localization of KATs is indicated. d | Lysine deacetylases (KDACs) are divided into two categories: the ‘classical’ Zn2+-dependent histone deacetylases (HDACs) and NAD+- dependent sirtuin deacetylases. KDACs can be further grouped into classes I, IIa, IIb, III and IV. The transcription factors TCF1 (T-cell-specific transcription factor 1) and LEF1 (lymphoid enhancer- binding factor 1) are recently reported KDACs that are unrelated to other KDACS. Subcellular localization of KDACs is indicated. The enzymes indicated with pink background either lack deacetylase activity or are involved in removing non-acetyl lysine acylations.

Fig. 2 | Biological processes regulated by non-histone protein acetylation (I). a | Acetylation of structural maintenance of chromosomes protein 3 (SMC3) by establishment of cohesion 1 homolog 1 (ESCO1) and ESCO2 promotes closing of the cohesin ring and chromatid cohesion. SMC3 is deacetylated by histone deacetylase 8 (HDAC8). b | Upon formation of DNA double- stranded breaks (DSB), TIP60 acetylates the kinase ataxia telangiectasia mutated (ATM), causing autophosphorylation and activation of ATM. Activated ATM phosphorylates multiple proteins, including TP53-binding protein 1 (53BP1) and ATP-citrate synthase (ACLY). Acetylation and

39 deacetylation of 53BP1 by CREB-binding protein (CBP) and HDAC2, respectively, controls its association with damaged chromatin. Additionally, TIP60-catalyzed acetylation of histone H2A Lys 15 (H2AK15ac) prevents binding of 53BP1 to chromatin. ACLY-dependent acetyl-CoA generation also promotes acetylation of histones and reduces binding of 53BP1 to chromatin. Inhibition of 53BP1 recruitment to chromatin impairs non-homologous end-joining (NHEJ)-dependent DSB repair. c | Acetylation of connector enhancer of kinase suppressor of ras 1 (CNK1) in its pleckstrin homology (PH) domain promotes its localization to the membrane, where it associates with the kinase RAF to promote phosphorylation and activation of ERK; this forms a feedback loop and stimulates CNK1 acetylation. In the insulin receptor (INSR) and insulin growth factor 1 receptor (IGF1R) signaling pathways, deacetylation of insulin receptor substrate 2 (IRS2) enhances its phosphorylation and activates ERK signaling. Phosphatidylinositol-3-kinase (PI3K) phosphorylates phosphatidylinositol (3,4)-diphosphate (PIP2) to generate phosphatidylinositol (3,4,5)- trisphosphate (PIP3), whereas the phosphatase PTEN converts PIP3 back into PIP2. Membrane- associated PIP3 recruits the kinases PDK1 and AKT through their PH domains. Site-specific acetylation of PTEN promotes its interaction with PDZ domain-containing proteins such as membrane-associated guanylate kinase inverted-2 (MAGI2), which enhance PTEN activity and promotes its recruitment to signaling complexes. Acetylation of PDK1 and AKT in their PH domains inhibits their membrane recruitment and activation. Acetylation of the mTORC2 subunit rapamycin-insensitive companion of mTOR (RICTOR) increases the kinase activity of mTORC2 towards its substrate AKT.

Fig. 3 | Biological processes regulated by non-histone protein acetylation (II). a | Alpha-tubulin is acetylated and deacetylated at Lys40 by tubulin acetyltransferase 1 (TAT1) and histone deacetylase 6 (HDAC6), respectively. TAT1 enters microtubules though their ends or thorough bending and breathing of the microtubule sidewall and stochastically acetylates -tubulin within the microtubule lumen. Acetylation increases mechanical resilience and prevents mechanical breakage of long-lived microtubules. b | Cortactin is acetylated at multiple residues in the nucleus by CREB-binding protein (CBP), and deacetylated by sirtuin 1 (SIRT1), SIRT2 and HDAC6. Deacetylated cortatin binds to KEAP1 and promotes cytoskeleton reorganization. c | During oxidative stress, CBP-catalyzed acetylation of the RNA-binding protein TDP43 causes its dissociation from RNA and promotes its aggregation. Oxidative stress causes formation of di-

40 sulfide bonds in TDP43 and in conditions of prolonged stress, TDP43 accumulates in a hyper- phosphorylated form. d | Acetylation of tau at Lys174 by CBP and p300 and at Lys280 through autocatalysis promotes tau aggregation, which is reversed by deacetylation of these residues by SIRT1 and HDAC6. Tau acetylation at Lys259 and Lys353 inhibits its phosphorylation at Ser262 and Ser356 and its aggregation. e | CBP acetylates cleavage factor Im 25 kDa subunit (CFIm25) and poly(A) polymerase (PAP), thereby inhibiting their interaction, and promoting the cytoplasmic localization of PAP through acetylation of its nuclear localization signal (NLS). Acetylation by CBP and p300 of CCR4-associated factor 1 (CAF1), a catalytic subunit of the CCR4–NOT1 deadenylase complex, promotes mRNA decay. Inhibition of HDAC1 and HDAC2 increases CAF1 acetylation and enhances mRNA decay.

Fig. 4 | Regulation of autophagy by non-histone protein acetylation. In conditions of nutrient starvation, glycogen synthase kinase-3 (GSK3) phosphorylates and activates TIP60, which promotes autophagy by acetylating the kinase ULK1. In nutrient rich conditions, mTORC1 phosphorylates and activates p300, which inhibits autophagy and promotes lipogenesis instead. p300 acetylates beclin 1, vacuolar protein sorting 34 (VPS34), autophagy protein 5 (ATG5), ATG7, microtubule-associated protein light chain 3 (LC3; ATG8 in yeast) and ATG12. Acetylation of ATG proteins inhibits the formation of autophagosomes. Acetylation of beclin 1 promotes recruitment of Rubicon to the UVRAG complex and inhibits autophagosome maturation. Sirtuin 1 (SIRT1) deacetylates the ATG proteins and beclin 1. SIRT1-catalyzed deacetylation of LC3 promotes its association with diabetes- and obesity-regulated gene (DOR) and export from the nucleus, and deacetylation of beclin1 promotes autophagosome maturation. Histone deacetylase 6 (HDAC6) promotes clearance of protein aggregates by facilitating their microtubule-based transport to autophagosomes. Additionally, HDAC6 deacetylates cortactin and promotes cortactin-dependent assembly of the F-actin network, which stimulates autophagosome-lysosome fusion.

Fig. 5 | Functional mechanisms of acetylation. a | The cytoplasmic acetyl-CoA synthetase 1 (AceCS1) and the mitochondrial AceCS2 are acetylated — possibly through autocatalysis — at Lys641 and Lys642, respectively, and deactivated. Deacetylation of AceCS1 and AceCS2 by sirtuin 1 (SIRT1) and SIRT3, respectively, restores their enzymatic function. Glucose-6-phosphate dehydrogenase (G6PD) is acetylated at Lys403 by lysine acetyltransferase 9 (KAT9) and

41 deacetylated by SIRT2. G6PD acetylation prevents its dimerization and inactivates it. b |Non- acetylated p300 is autoinhibited by interaction of the activation loop with the acetylatransferase (KAT) domain. Multisite autoacetylation of the activation loop displaces it away from the KAT domain and enhances the catalytic activity of p300. c | Non-acetylated E3 ubiquitin–protein ligase MDM2 can ubiquitylate itself. MDM2 acetylation by p300, at Lys182 and Lys185, recruits the deubiquitylase USP7, which deubiquitylates MDM2 and redirects the MDM2 activity towards its substrate p53. d | TIP60-catalyzed multisite acetylation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) promotes recruitment of E3 ubiquitin–protein ligase UHRF1, which targets DNMT1 to ubiquitin–proteasome-dependent degradation. Conversely, SMAD7 acetylation by p300, at Lys64 and Lys70, prevents its ubiquitylation by SMAD ubiquitination regulatory factor 1 (SMURF1) and subsequently its ubiquitylation-dependent proteasomal degradation. e | Acetylation of histone H4 Lys5 (H4K5) and H4K8 promotes bromodomain-containing protein 4 (BRD4) binding through its first bromodomain (BD1). The second bromodomain (BD2) of BRD4 interacts with the transcription factor Twist-related protein 1 (twist) acetylated at Lys73 and Lys76. BRD4 then recruits the positive transcription elongation factor b (P-TEFb) complex, which phosphorylates the carboxy-terminal domain of RNA polymerase II (Pol II) and activates gene transcription. f | Viral infection triggers p300-dependent acetylation of the viral-DNA sensor gamma-interferon-inducible protein 16 (IFI16) at Lys99 and Lys128, within its nuclear localization signal (NLS). Acetylation inhibits nuclear translocation, thereby preventing recognition of viral DNA in the nucleus by IFI16. TSA, trichostatin A.

Fig. 6 | Crosstalk between acetylation and other PTMs. a | SETD7-catalyzed methylation of p53 at Lys372 enhances its interaction with the acetyltransferase TIP60, which acetylates p53 at Lys120. p53 is also acetylated Lys382 by CBP and p300 and deacetylated by SIRT1. SETD7 binding inhibits SIRT1 activity and thereby prevents p53 deacetylation. b | Interaction of farnesoid X-activated receptor (FXR) with its agonist results in FXR sumoylation at Lys277 by the E3 SUMO ligase PIAS .

Sumoylated FXR associates with transcriptional co-repressors and with NF-B p65 subunit and inhibits transcription of proinflammatory genes. In nutrient rich conditions, FXR is acetylated at Lys217, which prevents FXR sumoylation and leads to activation of proinflammatory genes. c | Myocyte-specific enhancer factor 2A (MEF2A) is phosphorylated by cyclin-dependent-like kinase 5 (CDK5) at Ser408, which promotes of MEF2A sumoylation at Lys403 by PIASx. Sumoylated MEF2A

42 represses transcription and promotes dendritic maturation at neurons and synapse formation. Activation of calcium signaling causes dephosphorylation of MEF2A by the phosphatase calcineurin. Non-phosphorylated MEF2A is acetylated by CBP/p300. Acetylation and sumoylation target the same lysine residue (403) in MEF2A and thereby oppose each other. d | NF-B p65 is phosphorylated at Ser276 and Ser536 by MAPK and by I-kappa-B kinase 1 (IKK1) and IKK2, respectively. Phosphorylation promotes acetylation of p65 and transcription activation. e| p65 Lys310 deacetylation by sirtuin 1 (SIRT1) is necessary for its binding to histone-lysine N- methyltransferase SETD7, which methylates p65 at Lys314 and Lys315. Methylation of p65 is proposed to promote its ubiquitylation by an unknown ligase and its subsequent degradation by the proteasome. Acetylation of Lys310 by p300 neutralizes its positive charge and thus inhibits its interaction with SETD7 and p65 methylation. f | (FOXO1) is acetylated and deacetylated by CBP and SIRT2, respectively, at three different residues. Acetylation of FOXO1 attenuates its transcriptional activity and promotes its phosphorylation by AKT1 at Ser253. Phosphorylated FOXO1 interacts with 14-3-3, which retains FOXO1 in the cytoplasm.

Glossary terms: Lysine acylation: A term that collectively refers to the post-translational modification of lysine with different types of acyl-CoAs, such as acetyl-, butyryl-, propionyl-, succinyl-, glutaryl- and crotonyl-CoA. -amino side chain: The amino group located on the epsilon carbon of the lysine side chain. Bromodomain: A protein domain of ~110 amino acids that binds to acetylated lysine and is found in many proteins involved in transcription regulation. Cornelia de Lange syndrome: A genetic developmental disorder that is characterized by reduced growth, bone abnormalities and intellectual disability. PH domain: A protein domain found in diverse proteins involved in cell signaling and cytoskeleton formation; some of PH domains bind to phosphoinositides and thus recruit proteins to the plasma membrane.

43

Chaperone: A protein that assists in folding and unfolding of client proteins and thus contributes to the assembly and disassembly of macromolecular protein complexes. Acyl-stress: Cellular stress caused by accumulation of non-enzymatic lysine acylations. PDZ domain Protein-protein interaction domain that binds to short peptide sequences in interacting proteins. PDZ domain serves as scaffolds to assemble large multi-protein complexes, often at the cell membranes and cell-cell junctions. KIX domain A domain found in the acetyltransferases CREB-binding protein (CBP) and p300 that mediates interaction with phosphorylated cyclic AMP-responsive element-binding protein (CREB) and other transcription regulators. TUDOR domain A conserved protein–protein interaction domain that was first identified in the Drosophila melanogaster protein Tudor. Some of Tudor domains bind to methylated lysine or residues. YEATS domain A domain that is found in several chromatin-binding proteins, and some of YEATS domains bind to acetylated or crotonylated lysine. Double PHD finger (DPF) Tandem PHD finger, also known as double PHD finger (DPF), is a protein interaction domain that binds to acylated lysine residues.

44

Fig. 1

a CH CH + 3 3 NH3 C O C O + εCH KAT NH 2 NH NH CH3 3 δCH CH3 ε εCH 2 CH εCH 2 2 2 H O C O γ O 2 δ CH2 C δ δ CH2 CH2 SH CH2 HDACs 0− β + γ + γ CH2 S γ CH2 Non-enzymatic CH2 CoA CH2 α C CoA β β Sirtuins βCH N C CH CH 2 H 2 2 + O-acetyl- H O α α NAD αC C C ADP-ribose N C Lysine N H C N H C H H O H O + H O Nicotinamide Lysine Acetyl-lysine Acetyl-lysine

b FA synthesis Glucose Fatty acids Malonyl-CoA ACSS2 Acetate FA β-oxidation ACC1/2 Glycolysis ACSS2

PDC Acetyl-CoA Pyruvate Acetyl-CoA ACL Citrate Citrate ACL Acetyl-CoA Mitochondria Nucleus PDC Pyruvate

c

GCN5 p300 MYST Other Acetyltransferase family GCN5 (KAT2A) CBP (KAT3A) TIP60 (KAT5) TAT1 PCAF (KAT2B) p300 (KAT3B) KAT6A ESCO1 Subcellular localization KAT6B ESCO2 Nucleus KAT7 HAT1 (KAT1) Cytoplasm MOF (KAT8)

d Classical deacetylases Sirtuin deacetylases (Zn2+-dependent) (NAD+-dependent)

I IIa IIb IV III Other Deacetylase HDAC1 HDAC4 HDAC6 HDAC11 SIRT1 TCF1 class HDAC2 HDAC5 HDAC10 SIRT2 LEF1 HDAC3 HDAC7 SIRT3 HDAC8 HDAC9 Subcellular localization SIRT4 Nucleus SIRT5 Nucleolus SIRT6 Cytoplasm SIRT7 Mitochondria Fig. 2

Double strand break repair a Chromatid cohesion b

SMC3 P TIP60 ATM ATM Ac K3016

K1626 Ac 53BP1 ESCO1 and 2 HDAC8 Ac P K1628 ACYL K105 K106 CBP HDAC2 Ac Ac P Tip60 SMC3 53BP1

H2AK15ac Acetyl CoA Ac TIP60

NHEJ

c Cell signaling INSR / IGF1-R

PH Ac K414 PIP2 PI3K SIRT1 P PIP3 P CNK1 P P MAGI-2 PH c-RAF IRS2 IRS2 P PDZ- P P Ac PDK1 Ac containing proteins PH SIRT2 K415 P K402 Ac Ac Ac PTEN AKT1 P CBP K118 K292 K295 SIRT1 CBP P PCAF PH SIRT1 p300 PTEN CNK1 K495 K14 K20 Ac P Ac Ac PH High glucose Ac Ac K1116 PH PDK1 ERK High acetate K534 RICTOR Ac RICTOR K1119 AKT1 Ac Sirtuins K1125 mTORC2 mTORC2 Fig. 3

a b

bending Cytoplasm K40 and breathing Ac Ac Nucleus Cortactin

Ac Ac Ac TAT1 Ac Ac Ac Ac Ac SIRT1, SIRT2, HDAC6 KEAP1 Ac Ac Ac Ac Ac Ac Increased flexibility Cortactin Ac Cortactin HDAC6 and resilience to mechanical breakage Cortactin CBP, p300

Ac Ac Microtubule c Oxidative K145 stress Ac Ac Ac Ac Ac TDP-43 AcP Ac P

AA Prolonged P P

TDP-43 S-S TDP-43 S-S

stress TDP-43 S-S P CBP P TDP-43 S-S TDP-43 S-S TDP-43 S-S TDP-43 TDP-43 Ac TDP-43 TDP-43 Ac TDP-43 HDAC6 Ac Ac AAAAAA Ac P P AAAAAA AA

d K174 CBP/ Ac p300 Ac Ac SIRT1 Tau Tau Ac Tau K280 Tau Autocatalysis Ac Tau Tau HDAC6 Tau Tau

Tau p300 K259 Ac Ac Tau Ac Ac HDAC6 K353 P Tau P P P S356 Tau P S262 P Hyper-modified Tau aggregates

e RNA processing and stability K23 Ac CCR4-CAF1-NOT Ac Ac Ac CFIm Ac deadenylation complex CFIm25 NLS PAP CFIm KDACs NLS PAP CAF1a CFIm25 K736 K641 K650 CBP Ac Ac Ac Ac CBP/ p300 HDAC1/2 K740 NLS PAP K196 Ac K200 Ac Ac K203 Ac K206 pre-mRNA mRNA CAF1a AAAAAAAAAA Polyadenylation AAAAAAAAA Deadenylation Decay Gene AA AA AAAAAAAAAA A A Fig. 4

P Tip60 Tip60 GSK3 UVRAG Ac complex Rubicon UVRAG Starvation Nutrient-rich ATG5 Ac ATG16 Beclin1 P Ac Rubicon-UVRAG VPS34 mTORC1 ATG12 complex SIRT1 VPS15 p300 p300 UVRAG ATG7 Phagophore

p300 Lysosome / ATG8 Rubicon p300 Endosome Cytoplasm SIRT1 K430

Beclin1 Ac G VPS34 p300

Nucleus SIRT1 ATG16 VPS15 Ac

ATG5 Protein degradation K49 Ac ATG8

Ac K51 ATG7 ATG12 K437 Autophagosome- p300 G lysosome/ endosome ATG8 ATG8 fusion SIRT1 G G

DOR DOR ATG8 ATG8 Formation of ATG8

Aggregates F-actin network G P G VPS34 Beclin1 Cortactin ATG8 VPS15 ATG14L K162 Ac Ac Ub K771 K607 Cortactin K29 K781 p300 ULK1 HDAC6 Ac Ac Ac Motor proteins AcAc Ac Ac P HDAC6 Ac VPS34 Beclin1 Tip60 Microtuble Cortactin Ac VPS15 ATG14L Ac ULK1 Ac Ac Fig. 5

a Inhibition of catalytic activity Glucose-6-phosphate Acetate + NADP+ Active Inactive + Inactive CoA Active autocatalysis? G6PD KAT9 G6PD

AceCS1,2

AceCS1, 2 G6PD

Ac K403 Ac K403

SIRT1, SIRT3 Ac SIRT2 K641, K642 6-Phosphogluconate G6PD Acetyl-CoA + NADPH

b Enhancement of catalytic activity c Altered substrate specificity autoubiquitylation p53 ubiquitylation p300 Inactive Active MDM2 p53 autocatalysis MDM2 K182, CBP/p300 CBP/p300 Ub SIRT1 Ac Ac Ub Ub

KAT KAT K185 Ac SIRT2 Ac Ac USP7 Ac

d Enhanced protein degradation

Proteosome Proteosome TIP60 p300 SMAD7 SMAD7 SMAD7 DNMT1 Ac DNMT1 Ac DNMT1 TSA-sensitive Ub Ub Ac Ac Ac Ac KDAC HDAC1 AcAc Ub AcAc Ub Ub Ub Ub Ub K64, K70 SMURF1 Ub Ub UHRF1 Ub Ub

e Enhanced protein-protein interaction f Enhanced cytoplasmic localization

K99, K128 P-TEFb Cytoplasm Nucleus AcAc BRD4BRD4 BD1 BD2 P P P Gene transcription NLS IFI16 H4K5,K8 AcAc AcAc K73, K76 P Sensing of viral DNA P TWIST RNA PolII p300 TSA-sensitive KDAC

NLS IFI16

NLS IFI16 TIP60 TSA-sensitive KDAC

TWIST Fig. 6

a b SETD7 Nutrient FXR agonist TIP60 rich diet Sumoylation MeK372 Me Me AcK120 Co-repressors p53 p53 p53 PIASy Su K277 Su K217Ac K277 AcK382 FXR FXR FXR p65 FXR CBP/ p300 Transcriptional repression of proin ammatory SIRT1 genes SETD7

Dendrite maturation c and synapse formation d MAPK IKK1/2 S408 K403 K310 Su P S276 Ac P P P p300 P CDK5 PIASx P MEF2A MEF2A MEF2A RelA P RelA P RelA S536 Ca+ Calcineurin CBP/ p300 Ac K403 Gene transcription MEF2A MEF2A activation

K245 K248 e f CBP Ac Ac Attenuation of FOXO1 FOXO1 Ac K265 transcriptional activation K314, Sirt1 Set9 K315 K310 Ac K310 Me SIRT2 K310 Me AKT1 RelA RelA RelA p300 14-3-3 ? S256 Ac Ac P Ac Ac P Proteasome-dependent FOXO1 Ac FOXO1 Ac degradation

Cytoplasmic retention and degradation

Supplementary Figure 1. Functional networks of lysine acetyltransferase-regulated non- histone proteins. a| The network of functionally characterized, acetylated non-histone proteins and their acetyltransferases. In Supplementary Table 1, we manually curated a partial list of functionally-characterized acetylated mammalian proteins and their known

1 regulatory enzymes. The schematic illustrates networks of lysine acetyltransferase (KAT)– substrate relationships of these proteins. The substrates are color-coded based on their functions, as indicated. The interactions were visualized using the Cytoscape network analysis tool1. b| The bar chart shows the number of non-histone protein substrates targeted by the indicated KATs, as well as the fraction of the proteins that are linked to regulation of gene transcription.

2

Supplementary Figure 2. Functional networks of lysine deacetylase-regulated non-histone proteins. a| The network depicts lysine deacetylase (KDAC)–substrate relationships of functionally characterized non-histone proteins. The substrates are color-coded based on function, as indicated. The network was generated using a manually curated, partial list of 3 functionally characterized acetylated proteins in mammals, which are listed in Supplementary Table 1. The interactions were visualized using the Cytoscape network analysis tool1. b| The bar chart depicts the number of acetylated non-histone proteins targeted by the indicated KDACs, as well as the fraction of the proteins that are linked to regulation of gene transcription.

References: 1. Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498-2504 (2003).

4

Gene.Name..m Symbol Gene.name Category Canonical.Hum p53 TP53 tumor protein pTranscription faP04637-1 CRYAA CRYAA crystallin alpha Chaperone A0A140G945-1 EKLF KLF1 Kruppel like facTranscription faQ13351-1 p53 TP53 tumor protein pTranscription faP04637-1 p53 TP53 tumor protein pTranscription faP04637-1 HMG-I(Y) HMGA1 high mobility gDNA binding P17096-1 HMG-I(Y) HMGA1 high mobility gDNA binding P17096-1 GATA1 GATA1 GATA binding pTranscription faP15976-1 p53 TP53 tumor protein pTranscription faP04637-1 HMG-17 HMGN2 high mobility gDNA binding P05204-1 GATA1 GATA1 GATA binding pTranscription faP15976-1 NCOA3 NCOA3 nuclear receptoTranscription faQ9Y6Q9-1 TAF1B TAF1B TATA-box bindiDNA binding Q53T94-1 STAT6 STAT6 signal transducTranscription faP42226-1 MyoD MYOD1 myogenic diffeTranscription faP15172-1 C-MYB MYB MYB proto-oncTranscription faP10242-1 RELA RELA RELA proto-oncTranscription faQ04206-1 E2F1 transcriptioTranscription faQ01094-1 E2F1 E2F1 E2F transcriptioTranscription faQ01094-1 HMG-14 HMGN1 high mobility gDNA binding P05114-1 AR AR androgen recepTranscription faP10275-1 KPNA2 KPNA2 karyopherin suOthers P52292-1 EVI1 MECOM MDS1 and EVI1 Transcription faQ03112-7 HNF4 HNF4A hepatocyte nucTranscription faP41235-1 MyoD MYOD1 myogenic diffeTranscription faP15172-1 GATA3 GATA3 GATA binding pTranscription faP23771-1 CIITA CIITA class II major hiTranscription faP33076-1 C-MYB MYB MYB proto-oncTranscription faP10242-1 p53 TP53 tumor protein pTranscription faP04637-1 TAL1 TAL1 TAL bHLH transTranscription fa P17542-1 HMGN2 HMGN2 high mobility gDNA binding P05204-1 WRN WRN Werner syndroDNA binding Q14191-1 ER-α ESR1 estrogen recepTranscription faP03372-1 p53 TP53 tumor protein pTranscription faP04637-1 E2F1 E2F1 E2F transcriptioTranscription faQ01094-1 FOXO4 FOXO4 forkhead box OTranscription faP98177-1 HSP90 HSP90AA1 heat shock protChaperone P07900-1 NFE2 NFE2 nuclear factor, Transcription faQ16621-1 EKLF KLF1 Kruppel like facTranscription faQ13351-1 HSP90 HSP90AA1 heat shock protChaperone P07900-1 ER-α ESR1 estrogen recepTranscription faP03372-1 CRYAB CRYAB crystallin alpha Chaperone P02511-1 p63 TP63 tumor protein pTranscription faQ9H3D4-1 FEN1 FEN1 flap structure-sNuclease P39748-1 pRB RB1 RB transcriptioSignaling P06400-1 YY1 YY1 YY1 transcriptioTranscription faP25490-1 HMG-I(Y) HMGA1 high mobility gDNA binding P17096-1 HMG-I(Y) HMGA1 high mobility gDNA binding P17096-1 RIP140 NRIP1 nuclear receptoTranscription faP48552-1 p53 TP53 tumor protein pTranscription faP04637-1 NFKB1 NFKB1 nuclear factor kTranscription fa P19838-1 TP73 tumor protein pTranscription faO15350-1 SP3 SP3 Sp3 transcriptioTranscription faQ02447-1 DEK DEK DEK proto-oncoRNA binding/prQ8RVL2-1 TDG TDG thymine DNA g DNA binding Q13569-1 CTNNB1 CTNNB1 catenin beta 1 Transcription faP35222-1 AR AR androgen recepTranscription faP10275-1 TUBA1A1 TUBA1A tubulin alpha 1 Cytoskelton Q71U36-1 IRF7 IRF7 interferon reguTranscription faQ92985-1 BCL6 BCL6 CLL/lympTranscription faP41182-1 SMAD7 SMAD7 SMAD family mTranscription faO15105-1 RELA RELA RELA proto-oncTranscription faQ04206-1 ATM ATM ATM serine/thrKinase Q13315-1 RELA RELA RELA proto-oncTranscription faQ04206-1 HIF1A HIF1A hypoxia inducibTranscription faQ16665-1 p53 TP53 tumor protein pTranscription faP04637-1 CREB CREB1 cAMP responsivTranscription faP16220-1 PLAG1 PLAG1 PLAG1 zinc fingTranscription faQ6DJT9-1 TUBA1A1 TUBA1A tubulin alpha 1 Cytoskelton Q71U36-1 SREBP1 SREBF1 sterol regulatorTranscription faP36956-1 IRF2 IRF2 interferon reguTranscription faP14316-1 KLF13 KLF13 Kruppel like facTranscription faQ9Y2Y9-1 PCAF KAT2B lysine acetyltraKAT Q92831-1 ER81 ETV1 ETS variant 1 Transcription faP50549-1 CART1 ALX1 ALX Transcription faQ15699-1 PLAGL2 PLAGL2 PLAG1 like zinc Transcription faQ9UPG8-1 TFIIB GTF2B general transcrKAT Q00403-1 p53 TP53 tumor protein pTranscription faP04637-1 FOXO4 FOXO4 forkhead box OTranscription faP98177-1 HMGB1 HMGB1 high mobility gDNA binding P09429-1 KLF5 KLF5 Kruppel like facTranscription faQ13887-1 APE1 APEX1 apurinic/apyrimNuclease P27695-1 BETA2 NEUROD1 neuronal differTranscription faQ13562-1 ZNF76 ZNF76 protTranscription faP36508-1 RUNX1 RUNX1 runt related traTranscription faQ01196-1 p53 TP53 tumor protein pTranscription faP04637-1 FOXO3 FOXO3 forkhead box OTranscription faO43524-1 CEBPB CEBPB CCAAT enhanceTranscription faP17676-1 GATA2 GATA2 GATA binding pTranscription faP23769-1 p300 EP300 E1A binding proKAT Q09472-1 HMGB1 HMGB1 high mobility gDNA binding P09429-1 HMGB2 HMGB2 high mobility gDNA binding P26583-1 KU70 XRCC6 X-ray repair croDNA binding P12956-1 pRB RB1 RB transcriptioSignaling P06400-1 CTNNB1 CTNNB1 catenin beta 1 Transcription faP35222-1 RUNX3 RUNX3 runt related traTranscription faQ13761-1 RELA RELA RELA proto-oncTranscription faQ04206-1 NEIL2 NEIL2 nei like DNA glyDNA binding Q969S2-1 FOXO1 FOXO1 forkhead box OTranscription faQ12778-1 NFE4 NFE4 nuclear factor, Transcription faQ86UQ8-1 SRY SRY sex determininTranscription faQ05066-1 HNF6 ONECUT1 one cut homeoTranscription faQ9UBC0-1 C- MYC MYC proto-oncTranscription faP01106-1 ER-α ESR1 estrogen recepTranscription faP03372-1 STAT3 STAT3 signal transducTranscription faP40763-1 STAT3 STAT3 signal transducTranscription faP40763-1 PGC1A PPARGC1A PPARG coactivaTranscription faQ9UBK2-1 MEF2C MEF2C myocyte enhanTranscription faQ06413-1 FOXO1 FOXO1 forkhead box OTranscription faQ12778-1 NPM1 NPM1 nucleophosmin Membrane proP06748-1 RELA RELA RELA proto-oncTranscription faQ04206-1 RUNX2 RUNX2 runt related traTranscription faQ13950-1 GCM1 GCM1 glial cells missinTranscription faQ9NP62-1 PU.1 SPI1 Spi-1 proto-oncTranscription faP17947-1 PGC1A PPARGC1A PPARG coactivaTranscription faQ9UBK2-1 SMAD2 SMAD2 SMAD family mTranscription faQ15796-1 CD38 CD38 CD38 molecule Others P28907-1 ATF4 ATF4 activating transTranscription fa P18848-1 KLF6 KLF6 Kruppel like facTranscription faQ99612-1 C-MYC MYC MYC proto-oncTranscription faP01106-1 FOXO1 FOXO1 forkhead box OTranscription faQ12778-1 SF1 SF1 splicing factor 1Transcription faQ13285-1 CTBP2 CTBP2 C-terminal bindTranscription faP56545-1 pRB RB1 RB transcriptioSignaling P06400-1 OGG1 OGG1 8-oxoguanine DDNA binding O15527-1 SP1 SP1 Sp1 transcriptioTranscription faP08047-1 STAT1 STAT1 signal transducTranscription faP42224-1 ER-α ESR1 estrogen recepTranscription faP03372-1 ABL1 ABL1 ABL proto-oncoKinase P00519-1 STAT3 STAT3 signal transducTranscription faP40763-1 HDAC1 HDAC1 histone deacetyKDAC Q13547-1 FOXP3 FOXP3 forkhead box P Transcription faQ9BZS1-1 AceCS2 ACSS2 acyl-CoA syntheMetabolic enzyQ9NR19-1 ATG5 ATG5 autophagy relaUbi/Sumo/Atg8 Q9H1Y0-1 AceCS1 ACSS1 acyl-CoA syntheMetabolic enzyQ9NUB1-1 AceCS2 ACSS2 acyl-CoA syntheMetabolic enzyQ9NR19-1 PTEN PTEN phosphatase anPhosphatase P60484-1 ATG7 ATG7 autophagy relaUbi/Sumo/Atg8 O95352-1 GATA1 GATA1 GATA binding pTranscription faP15976-1 LC3B MAP1LC3B microtubule asUbi/Sumo/Atg8 Q9GZQ8-1 SMAD3 SMAD3 SMAD family mTranscription faP84022-1 p53 TP53 tumor protein pTranscription faP04637-1 p53 TP53 tumor protein pTranscription faP04637-1 WRN WRN Werner syndroDNA binding Q14191-1 SMAD2 SMAD2 SMAD family mTranscription faQ15796-1 SMAD3 SMAD3 SMAD family mTranscription faP84022-1 CEBPB CEBPB CCAAT enhanceTranscription faP17676-1 CFIm25 NUDT21 nudix hydrolaseRNA binding/prO43809-1 PAP PAPOLA poly(A) polymeRNA binding/prP51003-1 p53 TP53 tumor protein pTranscription faP04637-1 p53 TP53 tumor protein pTranscription faP04637-1 MAX MAX MYC associatedTranscription faP61244-1 ATG12 ATG12 autophagy relaUbi/Sumo/Atg8 O94817-1 ATG5 ATG5 autophagy relaUbi/Sumo/Atg8 Q9H1Y0-1 ATG7 ATG7 autophagy relaUbi/Sumo/Atg8 O95352-1 HSP90 HSP90AA1 heat shock protChaperone P07900-1 LC3B MAP1LC3B microtubule asUbi/Sumo/Atg8 Q9GZQ8-1 PCAF KAT2B lysine acetyltraKAT Q92831-1 MAML1 MAML1 mastermind likTranscription faQ92585-1 HDAC6 HDAC6 histone deacetyKDAC Q9UBN7-1 PARP1 PARP1 poly(ADP-ribosOthers P09874-1 PARP1 PARP1 poly(ADP-ribosOthers P09874-1 FOXO4 FOXO4 forkhead box OTranscription faP98177-1 TP2 TNP2 transition proteOthers Q05952-1 TUBA1A1 TUBA1A tubulin alpha 1 Cytoskelton Q71U36-1 BACE1 BACE1 beta-secretase Membrane proP56817-1 CDK9 CDK9 cyclin dependeKinase P50750-1 ATF2 ATF2 activating transTranscription fa P15336-1 NBS1 NBN Nibrin Nuclease O60934-1 NOTCH1 NOTCH1 notch 1 Membrane proP46531-1 Cortactin CTTN cortactin Signaling Q14247-1 RXRα RXRA retinoid X recepTranscription faP19793-1 eNOS NOS3 nitric oxide synOthers P29474-1 FLI1 FLI1 Fli-1 proto-oncoTranscription faQ01543-1 IRS2 IRS2 insulin receptoSignaling Q9Y4H2-1 IFNaR2 IFNAR2 interferon alphMembrane proP48551-1 ATM ATM ATM serine/thrKinase Q13315-1 LXRA NR1H3 nuclear receptoTranscription faQ13133-1 LXRB NR1H2 nuclear receptoTranscription faP55055-1 SP1 SP1 Sp1 transcriptioTranscription faP08047-1 p53 TP53 tumor protein pTranscription faP04637-1 BTK BTK Bruton tyrosineKinase Q06187-1 NR1D2 NR1D2 nuclear receptoTranscription faQ14995-1 RPS6KB1 RPS6KB1 ribosomal proteKinase P23443-1 BMAL1 ARNTL aryl hydrocarboTranscription faO00327-2 p53 TP53 tumor protein pTranscription faP04637-1 GATA4 GATA4 GATA binding pTranscription faP43694-1 p53 TP53 tumor protein pTranscription faP04637-1 PARP2 PARP2 poly(ADP-ribosOthers Q9UGN5-1 MKP1 DUSP1 dual specificity Phosphatase P28562-1 PRX1 PRDX1 peroxiredoxin 1Signaling Q06830-1 PRX2 PRDX2 peroxiredoxin 2Signaling P32119-1 SMC3 SMC3 structural mainOthers Q9UQE7-1 PML PML promyelocytic lOthers P29590-1 PTEN PTEN phosphatase anPhosphatase P60484-1 Cortactin CTTN cortactin Signaling Q14247-1 p300 EP300 E1A binding proKAT Q09472-1 SATB1 SATB1 SATB homeoboTranscription faQ01826-1 NR3C1 NR3C1 nuclear receptoTranscription faP04150-1 RPS6KB2 RPS6KB2 ribosomal proteKinase Q9UBS0-1 FLI1 FLI1 Fli-1 proto-oncoTranscription faQ01543-1 HSF1 HSF1 heat shock tranTranscription fa Q00613-1 USF1 USF1 upstream transTranscription fa P22415-1 OTC OTC ornithine carbaMetabolic enzyP00480-1 CDC6 CDC6 cell division cycKinase Q99741-1 HTT HTT huntingtin Others P42858-1 FOXP3 FOXP3 forkhead box P Transcription faQ9BZS1-1 CyclinT1 CCNT1 cyclin T1 Signaling O60563-1 USF1 USF1 upstream transTranscription fa P22415-1 DNA2 DNA2 DNA replicationNuclease P51530-1 BUBR1 BUB1B BUB1 mitotic chKinase O60566-1 CyclinA CCNA2 cyclin A2 Signaling P20248-1 PGC1B PPARGC1B PPARG coactivaTranscription faQ86YN6-1 HIF2A EPAS1 endothelial PASTranscription faQ99814-1 TIP5 BAZ2A bromodomain DNA binding Q9UIF9-1 NPM1 NPM1 nucleophosmin Membrane proP06748-1 SOX2 SOX2 SRY-box 2 Transcription faP48431-1 14-3-3-ε YWHAE 3-monSignaling P62258-1 CDK1 CDK1 cyclin dependeKinase P06493-1 RTN-1C RTN1 reticulon 1 Others Q16799-3 CDK2 CDK2 cyclin dependeKinase P24941-1 TRα THRA thyroid hormonTranscription faP10827-1 MLCK MYLK myosin light chKinase Q15746-1 TIP60 KAT5 lysine acetyltraKAT Q92993-1 FXR NR1H4 nuclear receptoTranscription faQ96RI1-1 MRPL10 MRPL10 mitochondrial rOthers Q7Z7H8-1 Cortactin CTTN cortactin Signaling Q14247-1 GLI1 GLI1 GLI family zinc fTranscription faP08151-1 RELA RELA RELA proto-oncTranscription faQ04206-1 ASL ASL argininosuccinaMetabolic enzyP04424-1 eNOS NOS3 nitric oxide synOthers P29474-1 EH-HADH EHHADH enoyl-CoA hydrOthers Q08426-1 HSPA5 HSPA5 heat shock protChaperone P11021-1 Nur77 NR4A1 nuclear receptoTranscription faP22736-1 FOXO1 FOXO1 forkhead box OTranscription faQ12778-1 MDH MDH2 malate dehydroOthers P40926-1 FOXO1 FOXO1 forkhead box OTranscription faQ12778-1 DNMT1 DNMT1 DNA methyltraDNA binding P26358-1 LCAD ACADL acyl-CoA dehydMetabolic enzy P28330-1 EVI1 MECOM MDS1 and EVI1 Transcription faQ03112-1 CypA PPIA peptidylprolyl iOthers P62937-1 IDH2 IDH2 isocitrate dehydMetabolic enzyP48735-1 WRN WRN Werner syndroDNA binding Q14191-1 NR3B1 ESRRA estrogen relateTranscription faP11474-1 ARD1 NAA10 N(alpha)-acetylKAT P41227-1 PXR NR1I2 nuclear receptoTranscription faO75469-1 SREBP1 SREBF1 sterol regulatorTranscription faP36956-1 RPS6KB1 RPS6KB1 ribosomal proteKinase P23443-1 HIF1A HIF1A hypoxia inducibTranscription faQ16665-1 MTA1 MTA1 assoTranscription faQ13330-1 NFATC1 NFATC1 nuclear factor oOthers O95644-1 DDX17 DDX17 DEAD-box helicRNA binding/prQ92841-4 DDX5 DDX5 DEAD-box helicRNA binding/prP17844-1 RELA RELA RELA proto-oncTranscription faQ04206-1 FOXO3 FOXO3 forkhead box OTranscription faO43524-1 STAT1 STAT1 signal transducTranscription faP42224-1 PIP5K1C PIP5K1C phosphatidylin Membrane proO60331-1 XPA XPA XPA, DNA damaDNA binding P23025-1 RB2 RBL2 RB transcriptioSignaling Q08999-1 ThPOK ZBTB7B zinc finger and Transcription faO15156-1 SREBP1 SREBF1 sterol regulatorTranscription faP36956-1 BIRC5 BIRC5 baculoviral IAP Signaling O15392-1 CTIP RBBP8 RB binding protNuclease Q99708-1 GATA4 GATA4 GATA binding pTranscription faP43694-1 TAU MAPT microtubule asKAT P10636-8 pRB RB1 RB transcriptioSignaling P06400-1 PRLR PRLR prolactin Membrane proP16471-1 TUBA1A1 TUBA1A tubulin alpha 1 Cytoskelton Q71U36-1 RELA RELA RELA proto-oncTranscription faQ04206-1 EGFR EGFR epidermal growMembrane proP00533-1 C-MYC MYC MYC proto-oncTranscription faP01106-1 KCNB1 KCNB1 potassium voltaMembrane proQ14721-1 FOXO3 FOXO3 forkhead box OTranscription faO43524-1 HMGCS2 HMGCS2 3-hydroxy-3-meMetabolic enzyP54868-1 SOD2 SOD2 superoxide dismOthers P04179-1 SRSF2 SRSF2 serine and argiRNA binding/pr Q01130-1 PAX3 PAX3 paired box 3 Transcription faP23760-1 Cortactin CTTN cortactin Signaling Q14247-1 SOD2 SOD2 superoxide dismOthers P04179-1 NRF2 NFE2L2 nuclear factor, Transcription fa Q16236-1 CypD PPID peptidylprolyl iOthers Q08752-1 HMGB1 HMGB1 high mobility gDNA binding P09429-1 CX43 GJA1 gap junction prMembrane proP17302-1 PAX5 PAX5 paired box 5 Transcription faQ02548-1 KLF8 KLF8 Kruppel like facTranscription faO95600-1 ALDH2 ALDH2 aldehyde dehydMetabolic enzy P05091-1 TAU MAPT microtubule asKAT P10636-8 p38MAPK MAPK14 mitogen-activaKinase Q16539-1 NOTCH1 NOTCH1 notch 1 Membrane proP46531-1 p53 TP53 tumor protein pTranscription faP04637-1 GATA1 GATA1 GATA binding pTranscription faP15976-1 PEA3 ETV4 ETS variant 4 Transcription faP43268-1 UBTF UBTF upstream bindiTranscription faP17480-1 MOF KAT8 lysine acetyltraKAT Q9H7Z6-1 PKM2 PKM pyruvate kinaseSignaling P14618-1 RELA RELA RELA proto-oncTranscription faQ04206-1 GATA4 GATA4 GATA binding pTranscription faP43694-1 ALDH2 ALDH2 aldehyde dehydMetabolic enzy P05091-1 PEPCK1 PCK1 phosphoenolpyOthers P35558-1 AKT1 AKT1 AKT serine/threKinase P31749-1 PDK1 PDK1 pyruvate dehydKinase O15530-1 ABL1 ABL1 ABL proto-oncoKinase P00519-1 ATF5 ATF5 activating transTranscription fa Q9Y2D1-1 SDHA SDHA succinate dehyMetabolic enzyP31040-1 HIF1A HIF1A hypoxia inducibTranscription faQ16665-1 DNMT1 DNMT1 DNA methyltraDNA binding P26358-1 HBP1 HBP1 HMG-box transTranscription fa O60381-1 DAZAP1 DAZAP1 DAZ associated RNA binding/pr Q96EP5-1 MOF KAT8 lysine acetyltraKAT Q9H7Z6-1 PGC1A PPARGC1A PPARG coactivaTranscription faQ9UBK2-1 CREB CREB1 cAMP responsivTranscription faP16220-1 RICTOR RICTOR RPTOR indepenKinase Q6R327-1 NOTCH1 NOTCH1 notch 1 Membrane proP46531-1 NOTCH3 NOTCH3 notch 3 Membrane proQ9UM47-1 PGAM1 PGAM1 phosphoglyceraOthers P18669-1 TORC1 CRTC1 CREB regulated Signaling Q6UUV9-1 GP PYGL Glycogen PhospMetabolic enzyP06737-1 SPK1 SPHK1 sphingosine kinKinase Q9NYA1-1 ITPK1 ITPK1 inositol-tetrakisKinase Q13572-1 KU70 XRCC6 X-ray repair croDNA binding P12956-1 API5 API5 apoptosis inhibOthers Q9BZZ5-4 AR AR androgen recepTranscription faP10275-1 BIRC5 BIRC5 baculoviral IAP Signaling O15392-1 BUBR1 BUB1B BUB1 mitotic chKinase O60566-1 GLYATL2 GLYATL2 -N-acyltrOthers Q8WU03-1 HIPK2 HIPK2 homeodomain Kinase Q9H2X6-1 ULK1 ULK1 unc-51 like autoKinase O75385-1 SUMO1 SUMO1 small ubiquitin-Ubi/Sumo/Atg8 P63165-1 SUMO2 SUMO2 small ubiquitin-Ubi/Sumo/Atg8 P61956-1 UBTF UBTF upstream bindiTranscription faP17480-1 MOF KAT8 lysine acetyltraKAT Q9H7Z6-1 TIP60 KAT5 lysine acetyltraKAT Q92993-1 MEKK2 MAP3K2 mitogen-activaKinase Q9Y2U5-1 AIRE AIRE autoimmune reTranscription faO43918-1 MECP2 MECP2 methyl-CpG binTranscription faP51608-1 IFI16 IFI16 interferon gamTranscription faQ16666-1 KRAS KRAS KRAS proto-oncSignaling P01116-1 PGC1A PPARGC1A PPARG coactivaTranscription faQ9UBK2-1 AURORA-B AURKB aurora kinase BKinase Q96GD4-1 SKP2 SKP2 S-phase kinase Ubi/Sumo/Atg8 Q13309-1 eIF5A EIF5A eukaryotic tranTranslation initP63241-1 HDAC6 HDAC6 histone deacetyKDAC Q9UBN7-1 FANCJ BRIP1 BRCA1 interactDNA binding Q9BX63-1 PPARG PPARG peroxisome proTranscription faP37231-1 SMC3 SMC3 structural mainOthers Q9UQE7-1 MOF KAT8 lysine acetyltraKAT Q9H7Z6-1 EB1 MAPRE1 microtubule asSignaling Q15691-1 Myocardin MYOCD myocardin Transcription faQ8IZQ8-1 eIF5A2 EIF5A2 eukaryotic tranTranslation initQ9GZV4-1 GCN5 KAT2A lysine acetyltraKAT Q92830-1 p21 CDKN1A cyclin dependeSignaling P38936-1 CTNNB1 CTNNB1 catenin beta 1 Transcription faP35222-1 TRF2 TERF2 telomeric repeaDNA binding Q15554-3 SIK2 SIK2 salt inducible kKinase Q9H0K1-1 KRT8 KRT8 keratin 8 Cytoskelton P05787-1 USP22 USP22 ubiquitin specifOthers Q9UPT9-1 UBC9 UBE2I ubiquitin conjuUbi/Sumo/Atg8 P63279-1 FOXA2 FOXA2 forkhead box ATranscription faQ9Y261-1 HIF2A EPAS1 endothelial PASTranscription faQ99814-1 LDH-A LDHA lactate dehydroMetabolic enzyP00338-1 PSME3 PSME3 proteasome actOthers P61289-1 TCF4 TCF7L2 transcription faTranscription faQ9NQB0-1 TAU MAPT microtubule asKAT P10636-8 KRAS KRAS KRAS proto-oncSignaling P01116-1 TUBA1A1 TUBA1A tubulin alpha 1 Cytoskelton Q71U36-1 GLI2 GLI2 GLI family zinc fTranscription faP10070-5 HDAC1 HDAC1 histone deacetyKDAC Q13547-1 ACAT1 ACAT1 acetyl-CoA acetKAT P24752-1 XPG ERCC5 ERCC excision rNuclease P28715-1 CDK9 CDK9 cyclin dependeKinase P50750-1 ACLY ACLY ATP citrate lyasMetabolic enzyP53396-1 TDG TDG thymine DNA g DNA binding Q13569-1 TAU MAPT microtubule asKAT P10636-8 RFX5 RFX5 regulatory factoTranscription faP48382-1 KCNA5 KCNA5 potassium voltaMembrane proP22460-1 HOXA10 HOXA10 homeobox A10Transcription faP31260-1 BMAL1 ARNTL aryl hydrocarboTranscription faO00327-2 PKM2 PKM pyruvate kinaseSignaling P14618-1 DBC1 CCAR2 BMP/retinoic aSignaling Q8N163-1 KCNAB2 KCNAB2 potassium voltaMembrane proQ13303-1 CRYAB CRYAB crystallin alpha Chaperone P02511-1 FOXA2 FOXA2 forkhead box ATranscription faQ9Y261-1 PAF53 POLR1E RNA polymerasRNA binding/pr Q9GZS1-1 RNA PolII POLR2A RNA polymerasRNA binding/pr P24928-1 ATP5O ATP5PO ATP synthase pMembrane pro P48047-1 CypA PPIA peptidylprolyl iOthers P62937-1 PGR PGR progesterone r Transcription faP06401-1 TRIM50 TRIM50 tripartite motif Ubi/Sumo/Atg8 Q86XT4-1 MCM10 MCM10 minichromosomDNA binding Q7L590-1 AKT1 AKT1 AKT serine/threKinase P31749-1 RASSF5 RASSF5 Ras association Others Q8WWW0-1 OPA1 OPA1 OPA1, mitochoGTPase O60313-1 GAPDH GAPDH glyceraldehyde Metabolic enzy P04406-1 MTA2 MTA2 metastasis assoTranscription fa O94776-1 HMGB1 HMGB1 high mobility gDNA binding P09429-1 PDHA1 PDHA1 pyruvate dehydMetabolic enzy P08559-1 PDP1 PDP1 pyruvate dehyrMetabolic enzyQ9P0J1-1 TWIST TWIST1 twist family bHTranscription faQ15672-1 HDAC2 HDAC2 histone deacetyKDAC Q92769-1 PROM1 PROM1 prominin 1 Membrane proO43490-1 TBX5 TBX5 T-box 5 Transcription faQ99593-1 GCM1 GCM1 glial cells missinTranscription faQ9NP62-1 ETS1 ETS1 ETS proto-oncoTranscription faP14921-1 HSF1 HSF1 heat shock tranTranscription fa Q00613-1 MEK1 MAP2K1 mitogen-activaKinase Q02750-1 CDK5 CDK5 cyclin dependeKinase Q00535-1 MFN1 MFN1 mitofusin 1 GTPase Q8IWA4-1 IRF1 IRF1 interferon reguTranscription faP10914-1 G6PD G6PD glucose-6-phosMetabolic enzyP11413-1 BUBR1 BUB1B BUB1 mitotic chKinase O60566-1 TIP60 KAT5 lysine acetyltraKAT Q92993-1 MSH2 MSH2 mutS homolog DNA binding P43246-1 PCNA PCNA proliferating ceDNA binding P12004-1 HMGB1 HMGB1 high mobility gDNA binding P09429-1 PML PML promyelocytic lOthers P29590-1 6PGD PGD phosphogluconMetabolic enzyP52209-1 PRX1 PRDX1 peroxiredoxin 1Signaling Q06830-1 LON LONP1 lon peptidase 1Others P36776-1 CRABPII CRABP2 cellular retinoicTranscription faP29373-1 GABPB1 GABPB1 GA binding proTranscription faQ06547-1 MFN1 MFN1 mitofusin 1 GTPase Q8IWA4-1 BUBR1 BUB1B BUB1 mitotic chKinase O60566-1 HSPA5 HSPA5 heat shock protChaperone P11021-1 TIP60 KAT5 lysine acetyltraKAT Q92993-1 MSH4 MSH4 mutS homolog DNA binding O15457-1 SNAIL SNAI1 snail family tranTranscription faO95863-1 ALDH1A1 ALDH1A1 aldehyde dehydMetabolic enzy P00352-1 CREB CREB1 cAMP responsivTranscription faP16220-1 FXR NR1H4 nuclear receptoTranscription faQ96RI1-1 PGC1A PPARGC1A PPARG coactivaTranscription faQ9UBK2-1 HSP10 HSPE1 heat shock protChaperone P61604-1 TOPBP1 TOPBP1 DNA topoisomeSignaling Q92547-1 Ubiquitin UBC ubiquitin C Ubi/Sumo/Atg8P0CG48-1 HIPK2 HIPK2 homeodomain Kinase Q9H2X6-1 TDP43 TARDBP TAR DNA bindinOthers Q13148-1 IRF1 IRF1 interferon reguTranscription faP10914-1 ASPSCR1 ASPSCR1 ASPSCR1, UBX dOthers Q9BZE9-1 CEBPE CEBPE CCAAT enhanceTranscription faQ15744-1 NET1A NET1 neuroepithelial Others Q7Z628-1 LC3B MAP1LC3B microtubule asUbi/Sumo/Atg8 Q9GZQ8-1 MLL1 KMT2A lysine methyltrOthers Q03164-1 GOT2 GOT2 glutamic-oxaloaMetabolic enzyP00505-1 LC3B MAP1LC3B microtubule asUbi/Sumo/Atg8 Q9GZQ8-1 EZH2 EZH2 enhancer of zesOthers Q15910-1 LIN28 LIN28A lin-28 homolog RNA binding/prQ9H9Z2-1 VLCAD ACADVL acyl-CoA dehydMetabolic enzy P49748-1 OXCT OXCT1 3-oxoacid CoA-Metabolic enzy P55809-1 PLZF ZBTB16 zinc finger and Transcription faQ05516-1 MPP8 MPHOSPH8 M-phase phospMetabolic enzyQ99549-1 KAP1 TRIM28 tripartite motif Others Q13263-1 RORγt RORC RAR related orpTranscription faP51449-2 NAMPT NAMPT nicotinamide p Others P43490-1 MAT2A MAT2A adeMetabolic enzyP31153-1 Beclin 1 BECN1 beclin 1 Kinase Q14457-1 SOD1 SOD1 superoxide dismOthers P00441-1 TAF1B TAF1B TATA-box bindiDNA binding Q53T94-1 HSPA5 HSPA5 heat shock protChaperone P11021-1 RAN RAN RAN, member RGTPase P62826-1 RAN RAN RAN, member RGTPase P62826-1 GCPII FOLH1 folate hydrolasMembrane proQ04609-1 RAN RAN RAN, member RGTPase P62826-1 COMMD1 COMMD1 copper metaboTranscription faQ8N668-1 RAN RAN RAN, member RGTPase P62826-1 RAN RAN RAN, member RGTPase P62826-1 SSB1 NABP2 nucleic acid binDNA binding Q9BQ15-1 SOX2 SOX2 SRY-box 2 Transcription faP48431-1 RICTOR RICTOR RPTOR indepenKinase Q6R327-1 PTEN PTEN phosphatase anPhosphatase P60484-1 SOX4 SOX4 SRY-box 4 Transcription faQ06945-1 PGK1 PGK1 phosphoglyceraKinase P00558-1 TAU MAPT microtubule asKAT P10636-8 PLZF ZBTB16 zinc finger and Transcription faQ05516-1 NDPKD NME4 NME/NM23 nuOthers O00746-1 BCL6 BCL6 B cell CLL/lympTranscription faP41182-1 RORγt RORC RAR related orpTranscription faP51449-2 MPC1 MPC1 mitochondrial pMetabolic enzy Q9Y5U8-1 AKT1 AKT1 AKT serine/threKinase P31749-1 Cortactin CTTN cortactin Signaling Q14247-1 ATP6V1B2 ATP6V1B2 ATPase H+ tranOthers P21281-1 OLIG1 OLIG1 oligodendrocytTranscription fa Q8TAK6-1 GSK3B GSK3B glycogen synthKinase P49841-1 RhoGDIα ARHGDIA Rho GDP dissocOthers P52565-1 RhoGDIα ARHGDIA Rho GDP dissocOthers P52565-1 RhoGDIα ARHGDIA Rho GDP dissocOthers P52565-1 RhoGDIα ARHGDIA Rho GDP dissocOthers P52565-1 KLF4 Kruppel like facTranscription faO43474-3 RIG-I DDX58 DExD/H-box heRNA binding/pr O95786-1 PKM2 PKM pyruvate kinaseSignaling P14618-1 AURORA-B AURKB aurora kinase BKinase Q96GD4-1 ATRIP ATRIP ATR interacting Signaling Q8WXE1-1 PXR NR1I2 nuclear receptoTranscription faO75469-1 RRP9 RRP9 ribosomal RNA RNA binding/pr O43818-1 MFN2 MFN2 mitofusin 2 GTPase O95140-1 KLF7 KLF7 Kruppel like facTranscription faO75840-1 HSP70 HSPA4 heat shock protChaperone P0DMV8-1 GS GLUL glutamate-ammOthers P15104-1 FOXP3 FOXP3 forkhead box P Transcription faQ9BZS1-1 CEBPA CEBPA CCAAT enhanceTranscription faP49715-1 CEP76 CEP76 centrosomal prOthers Q8TAP6-1 PKM2 PKM pyruvate kinaseMetabolic enzyP14618-1 GAPDH GAPDH glyceraldehyde Metabolic enzy P04406-1 OCX SP7 Sp7 transcriptioTranscription faQ8TDD2-1 LSD1 KDM1A lysine demethyOthers O60341-1 TADA3 TADA3 transcriptional Transcription faO75528-1 TADA3 TADA3 transcriptional Transcription faO75528-1 FOXM1 FOXM1 forkhead box MTranscription faQ08050-1 HOXB9 HOXB9 homeobox B9 Transcription faP17482-1 SOX9 SOX9 SRY-box 9 Transcription faP48436-1 p53 TP53 tumor protein pTranscription faP04637-1 CAF1A CNOT7 chromatin asseRNA binding/pr Q9UIV1-1 KRAS KRAS KRAS proto-oncSignaling P01116-1 PYGO2 PYGO2 pygopus family Others Q9BRQ0-1 OCT4 POU5F1 POU class 5 homTranscription faQ01860-1 FOXO3 FOXO3 forkhead box OTranscription faO43524-1 HSP70 HSPA1A heat shock protChaperone P0DMV8-1 VGLL4 VGLL4 vestigial like famTranscription faQ14135-1 PLK4 PLK4 polo like kinase Kinase O00444-1 HSP70 HSPA4 heat shock protChaperone P0DMV8-1 NKX2.5 NKX2-5 NK2 homeobox Transcription faP52952-1 eIF2A EIF2S1 ukaryotic transTranslation init P05198-1 YARS YARS tyrosyl-tRNA syOthers P54577-1 TET2 TET2 tet methylcytosDNA binding Q6N021-1 LIFR LIFR LIF receptor alpMembrane proP42702-1 p66Shc SHC1 SHC adaptor prSignaling P29353-1 SCN5A SCN5A sodium voltageMembrane pro Q14524-1 MDM2 MDM2 MDM2 proto-oUbi/Sumo/Atg8Q00987-1 UBC9 UBE2I ubiquitin conjuUbi/Sumo/Atg8 P63279-1 GLI1 GLI1 GLI family zinc fTranscription faP08151-1 CIDEC CIDEC cell death inducMembrane pro Q96AQ7-1 SNAIL SNAI1 snail family tranTranscription faO95863-1 KIF11 KIF11 kinesin family mCytoskelton P52732-1 HINT1 HINT1 triad nSignaling P49773-1 IDH2 IDH2 Isocitrate DehyMetabolic enzyP48735-1 CAVIN1 CAVIN1 caveolae associMembrane pro Q6NZI2-1 MKL1 MKL1 megakaryoblasKinase Q969V6-1 IRS2 IRS2 insulin receptoSignaling Q9Y4H2-1 EGR2 EGR2 early growth reTranscription faP11161-1 DDB1 DDB1 damage specifiUbi/Sumo/Atg8 Q16531-1 VDR VDR vitamin D recepTranscription faP11473-1 GLI1 GLI1 GLI family zinc fTranscription faP08151-1 EGR2 EGR2 early growth reTranscription faP11161-1 DDX21 DDX21 DExD-box helicRNA binding/prQ9NR30-1 DDB1 DDB1 damage specifiUbi/Sumo/Atg8 Q16531-1 AMPAR GRIA1 glutamate ionoMembrane pro P42261-1 SIRT3 SIRT3 sirtuin 3 KDAC Q9NTG7-1 CNK1 CNKSR1 connector enhaMembrane pro Q969H4-1 VPS34 PIK3C3 phosphatidylinMembrane pro Q8NEB9-1 ETS1 ETS1 ETS proto-oncoTranscription faP14921-1 PRAK MAPKAPK5 mitogen-activaKinase Q8IW41-1 RPA1 RPA1 replication protDNA binding P27694-1 RPA1 RPA1 replication protDNA binding P27694-1 SMN STMN1 stathmin 1 Others P16949-1 AURORA-A AURKA aurora kinase AKinase O14965-1 SIRT1 SIRT1 sirtuin 1 KDAC Q96EB6-1 SAMHD1 SAMHD1 SAM and HD doOthers Q9Y3Z3-1 ASS1 ASS1 argininosuccinaMetabolic enzy P00966-1 PKM2 PKM pyruvate kinaseSignaling P14618-1 PKM2 PKM pyruvate kinaseSignaling P14618-1 TRXR1 TXNRD1 thioredoxin redMetabolic enzyQ16881-1 TBX5 TBX5 T-box 5 Transcription faQ99593-1 SMAD2 SMAD2 SMAD family mTranscription faQ15796-1 53BP1 TP53BP1 tumor protein pSignaling Q12888-1 GKRP GCKR Glucokinase ReMetabolic enzyQ14397-1 GCPII FOLH1 folate hydrolasMembrane proQ04609-1 GATA3 GATA3 GATA binding pTranscription faP23771-1 SMAD3 SMAD3 SMAD family mTranscription faP84022-1 FBXL19 FBXL19 F-box and leuciUbi/Sumo/Atg8 Q6PCT2-1 c-SRC SRC SRC proto-oncoKinase P12931-1 TPX2 TPX2 TPX2, microtubCytoskelton Q9ULW0-1 NOTCH1 NOTCH1 notch 1 Membrane proP46531-1 ATG5 ATG5 autophagy relaUbi/Sumo/Atg8 Q9H1Y0-1 RAD52 RAD52 RAD52 homoloDNA binding P43351-1 TOP2A TOP2A DNA topoisomeDNA binding P11388-1 CYP19A1 CYP19A1 Aromatase Metabolic enzyP11511-1 SRSF5 SRSF5 serine and argiRNA binding/pr Q13243-1 STAT3 STAT3 signal transducTranscription faP40763-1 HSP90 HSP90AA1 heat shock protChaperone P07900-1 p53 TP53 tumor protein pTranscription faP04637-1 MEF2D MEF2D myocyte-specifTranscription faQ14814-1 HIC1 HIC1 hypermethylateTranscription faQ14526-2 Sites(Canonical.Human.Uni Species Sites (in Refs) KAT KDAC K370, K372, K373, K381, K3 Human K370, K372, K3CBP, p300 K70 Human K70 K265, K274 Human K279, K288 CBP, p300 K320 Human K320 PCAF K382 Human K382 p300 K65 Human K65 CBP K71 Human K71 PCAF K308, K312, K314 Chicken K214, K218, K2 p300 K320, K373 Human K320, K373 CBP, p300, PCAF K3 Human K3 PCAF K245, K246, K252, K312 Mouse K245, K246, K2CBP K619, K620 Human K629, K630 p300 NA Human NA PCAF NA Human NA CBP, p300 K99, K102, K104 Mouse K99, K102, K10 PCAF K471, K480, K485 Human K471, K480, K4 p300 NA Human NA CBP, p300 HDAC3 K117, K120, K125 Human K117, K120, K1 CBP, p300, PCAF K117, K120, K125 Human K117, K120, K1 CBP, p300 HDAC1 K3, K31, K38, K42, K55, K59Human K2, K30, K37, Kp300 K612, K613 Human K632, K633 CBP, p300 K22 Human K22 CBP, p300 NA Human NA CBP, PCAF K106, K108, K 126, K127 Mouse K97, K99, K117, K118 K99, K102 Mouse K99, K102 CBP, p300 K304 Mouse K305 p300 K141, K144 Human K141, K144 CBP, PCAF K442, K445 Mouse K438, K441 CBP K370, K372, K373, K381, K3 Human K370, K372, K373, K381, K382 HDAC1 K221, K222 Human K221, K222 p300, PCAF NA Human NA NA Human NA p300 NA Human NA HDAC1 NA Human NA HDAC1, SIRT1 NA Human NA CBP, p300 NA Human NA CBP SIRT1 NA Human NA HDAC6 K53, K60, K71, K76 Human K53, K60, K71, CBP K274, K288 Mouse K288, K302 CBP, p300 NA Human NA HDAC6 K299, K302, K303 Human K299, K302, K3 p300 K92 Human K92 NA Human NA p300 K354, K375, K377, K380 Human K354, K375, K3p300 K873, K874 Human K873, K874 p300 K173, K174, K178, K179, K1Human K173, K174, K1CBP, p300, PCA HDAC1, HDAC2 K65 Human K65 CBP K71 Human K71 GCN5, PCAF K446 Human K446 CBP, p300 K382 Human K382 SIRT1 K431, K440, K441 Human K431, K440, K4 CBP, p300 K321, K327, K331 Human K321, K327, K3 p300 K551 Human K551 CBP, p300 NA Human NA PCAF K83, K84, K87 Mouse K94, K95, K98 CBP, p300 K49 Human K49 CBP K631, K633, K634 Human K630, K632, K6 p300, PCAF, TIPHDAC1 K40 Mouse K40 HDAC6 K92 Human K92 GCN5, PCAF K379 Human K379 p300 K64, K70 Human K64, K70 p300 K122, K123 Human K122, K123 p300, PCAF HDAC3 NA Human NA TIP60 K218, K221, K310 Human K218, K221, K310 K532 Human K532 ARD1 K373, K382 Human K373, K382 p300 K91, K94, K136 Human K91, K94, K136 CBP NA Human NA p300 HDAC7 K40 Human K40 SIRT2 K324, K333 Human K324, K333 p300 K75, K78 Human K75, K78 CBP, p300 K225, K226, K234 Human K226, K227, K2 CBP, p300, PCAF K416, K428, K430, K441, K4 Human K416, K428, K4PCAF K33, K116 Human K33, K116 p300, PCAF K131 Human K131 CBP, p300 NA Human NA p300 HDAC7 K238 Human K238 TFIIB K320, K373, K382 Mouse K317, K370, K379 SIRT1 K186, K189, K407 Human K186, K189, K4 CBP K28, K29, K30, K182, K183, Bovine K28, K29, K30, CBP, p300, PCAF K369 Human K369 p300 K6, K7 Human K6, K7 p300 K132, K135, K138, K160, K1 Human K132, K135, K1PCAF NA Human NA p300 HDAC1 K24, K43 Human K24, K43 p300 K382 Human K382 CBP K242, K259, K270, K290, K5 Human K242, K259, K270, K290, K569 SIRT1 NA Human NA p300 K102, K281, K285, K334, L3Human K102, K281, K2p300, PCAF K1499 Human K1499 p300 K3 Human K2 CBP K3 Human K2 CBP K539, K542, K544, K553, K5 Human K539, K542, K5CBP, PCAF K873, K874 Human K873, K874 p300 K345 Human K345 p300 K148, K186, K192 Human K148, K186, K1 p300 HDAC4, HDAC5 K310 Human K310 SIRT1 K50, K154 Human K49, K153 p300 K245, K248, K265 Mouse K242, K245, K2 CBP SIRT2 K43 Human K43 PCAF K136 Human K136 p300 HDAC3 K339 Human K339 CBP K323 Mouse K323, K417 GCN5, PCAF, TIP60 K303 Human K303 p300 K685 Human K685 CBP, p300 K685 Human K685 p300 HDAC1, HDAC2 K79, K146, K184, K254, K27Mouse K77, K144, K183, K253, K270, KSIRT1 K116, K119, K234, K239, K2Human K116, K119, K2p300 K245, K248, K265 Mouse K242, K245, K2 CBP SIRT2 K212, K229, K230, K250, K2Human K212, K229, K2p300 K310 Human K310 p300 NA Human NA p300 HDAC4, HDAC5 K367, K406, K409 Human K367, K406, K4 CBP K168, K169, K204, K206 Mouse K170, K171, K2p300 NA Human NA GCN5 NA Human NA CBP, p300 NA Human NA SIRT1 K311 Human K311 p300 K209 Human K209 CBP, p300 K143, K148, K157, K275, K3Mouse K144, K149, K1GCN5, p300 NA Human NA SIRT2 K106, K109, K110 Human K102, K105, K1 p300 K10 Human K10 p300 K873, K874 Human K873, K874 p300 K338, K341 Human K338, K341 p300 K703 Human K703 p300 HDAC1 K410, K413 Human K410, K413 CBP K266, K268 Human K266, K268 p300 K711 Human K730 CBP, p300, PCAF K685 Human K685 p300 K218, K220, K432, K438, K4Human K218, K220, K4p300 NA Mouse NA K661 Human K642 SIRT3 NA Human NA SIRT1 K642 Mouse K661 SIRT3 K661 Mouse K635 Recombinant PSIRT1 K125, K128 Human K125, K128 PCAF NA Human NA SIRT1 K245, K246, K252, K312 Human K245, K246, K252, K312 NA Human NA SIRT1 K378 Human K378 K320 Mouse K317 PCAF K320, K373 Mouse K317, K370, K379 HDAC3 NA Human NA p300 K19 Human K19 CBP, p300, PCAF K19 Human K19 CBP, p300, PCASIRT1 K43 Mouse K39 CBP, p300 K23 Human K23 CBP HDAC1, HDAC3 K641, K650, K736, K740 Bovine K635, K644, K7CBP HDAC1, HDAC3 K120 Human K120 TIP60 K120 Human K120 MOF, TIP60 K57, K153, K154 Human K57, K144, K14 p300 NA Human NA p300 NA Human NA p300 NA Human NA p300 K294 Human K294 HDAC6 NA Human NA p300 NA Human NA SIRT1 K138, K139, K188, K189 Human K138, K139, K1p300 NA Human NA p300 NA Human NA PCAF SIRT1 NA Human NA p300 NA Human NA NA Human NA p300 K40 Mouse K40 HDAC6 K126, K275, K279, K285, K2Human K126, K275, K2CBP, p300 K44 Human K44 p300 HDAC3 K357, K374 Human K357, K374 p300 K208, K233, K334, K441, K5Human K208, K233, K3p300, PCAF SIRT1 K2029, K2049, K2054, K207Human K2019, K2039, TIP60 K87, K124, K161, K198, K23Human K87, K124, K16PCAF HDAC6 K145 Human K145 p300 K494, K504 Bovine K496, K506 SIRT1 K380 Human K380 CBP, p300 K118, K292, K295, K415 Mouse K118, K289, K292, K412 SIRT1 K399 Human K399 CBP K3016 Human K3016 TIP60 K434 Mouse K432 SIRT1 K447 Mouse K433 SIRT1 NA Rat NA K373, K382 Human K373, K382 NA Mouse NA p300 HDAC1 K162, K163 Human K161, K162 TIP60 HDAC1 NA Human NA p300, PCAF K538 Mouse K537 CLOCK K382 Mouse K382 SIRT7 K312, K319, K321, K323 Mouse K311, K318, K3p300 K120, K373, K382 Mouse K117, K370, K3 TIP60 K37, K38 Mouse K36, K37 GCN5L, PCAF K57 Mouse K57 p300 K197 Human K197 HDAC6 K196 Human K196 HDAC6 K105, K106 Human K105, K106 ESCO1 K487, K515 Human K487, K515 p300 K402 Human K402 CBP SIRT1 K87, K124, K161, K189, K19Human K87, K124, K16p300 SIRT1 K418, K423, K1542, K1546, Human K418, K423, K1p300 SIRT2 K136 Human K136 PCAF K480, 492, K494, K495 Human K480, 492, K49CLOCK NA Human NA p300, PCAF K380 Human K380 PCAF K80 Human K80 SIRT1 K235 Human K237 PCAF HDAC9 K88 Human K88 SIRT3 K92, K105, K109 Human K92, K105, K10 GCN5 K443 Mouse K444 NA Human NA SIRT1 K380, K386, K390, K404 Human K380, K386, K3p300 K199 Human K199 NA Human NA p300 K250 Human K250 PCAF K54, K68, K95, K112 Human K54, K68, K95, PCAF K202, K218, K454, K468, K6Mouse K202, K218, K4GCN5 SIRT1 K385, K685, K741 Human K385, K685, K741 SIRT1 K680 Mouse K633 SIRT1 K212, K215, K229, K230, K2Human K212, K215, K2p300 SIRT1 K73 Mouse K75 K118, K123 Human K118, K123 K33 Human K33 K204 Human K204 K33 Mouse K33 PCAF K130, K134, K136 Chicken K128, K132, K1 CBP K608 Human K608 ARD1 NA Human NA SIRT1 K217 Human K217 p300 SIRT1 K46, K124, K162, K169, K19 Human K46, K124, K162, K169, K196 SIRT3 K87, K124, K161, K189, K19Human K87, K124, K161, K189, K198, KHDAC6 K518 Human K518 HDAC1 K310 Human K310 SIRT1 K288 Human K288 NA Human NA SIRT1 K165, K171, K346, K584 Human K165, K171, K346, K584 NA Human NA HDAC6 NA Human NA p300 HDAC1 NA Human NA SIRT2 K185, K301, K307, K314 Human K185, K301, K307, K314 NA Mouse NA SIRT1 NA Human NA TIP60 HDAC1 K42 Mouse K42 SIRT3 K564 Human K564 CBP, p300 K125 Human K125 NA Mouse NA SIRT3 K366, K887, K1117, K1127, Human K366, K887, K1CBP, p300 SIRT1 K129, K138, K160, K162 Human K129, K138, K1PCAF HDAC8, SIRT1 K29, K136, K198 Human K29, K136, K19 ARD1 NA Human NA SIRT1 K324, K333 Human K324, K333 SIRT1 K516 Human K516 K674 Human K674 PCAF SIRT1 K626 Human K626 NA Human NA p300, PCAF HDAC5 K108, K109, K121 Human K108, K109, K1 p300 K32, K33, K40, K43, K45 Human K32, K33, K40, p300 NA Mouse NA HDAC1, HDAC2 NA Mouse NA HDAC3 NA Human NA HDAC4 K265, K268 Human K265, K268 SIRT1 K63, K67 Human K63, K67 SIRT1 K1083 Mouse K1079 p300 K206, K212, K335 Mouse K210, K216, K3 p300 K313, K333 Human K289, K309 p300 SIRT1 K129 Human K129 K432, K526, K604 Human K432, K526, K604 SIRT6 K312, K319, K321, K323 Mouse K311, K318, K320, K322 HDAC2 K163, K174, K180 Human K163, K174, K1 p300 SIRT1 K873, K874 Human K873, K874 PCAF K277 Human K277 CBP HDAC6, SIRT2 K40 Human K40 TAT1 K310 Human K310 SIRT2 K708, K860, K867 Human K684, K836, K8 CBP NA Human NA SIRT1 NA Human NA CBP NA Human NA SIRT1, SIRT2 K310, K447, K473 Human K310, K447, K473 SIRT3 K53, K89 Human K53, K89 SIRT3 K52 Human K52 TIP60 HDAC6 K437, K475 Mouse K437, K475 SIRT1 NA Human NA HDAC6 K122 Mouse K122 SIRT3 K596, K599 Mouse K588, K591 CBP SIRT1 K145 Mouse K166 SIRT3 K3 Human K2 K9, K234, K264 Mouse K9, K234, K264 PCAF K5, K67, K79, K87, K89, K94Human K5, K67, K79, Kp300 K67, K93, K95 Human K67, K93, K95 p300, PCAF NA Human NA SIRT3 K280 Human K280 HDAC6 K53, K152 Human K53, K152 p300, PCAF HDAC3 K1774, K1780, K1781, K178Mouse K1764, K1770, p300, PCAF SIRT1 K120 Human K120 K312, K314, K315, K316 Mouse K312, K314, K3CBP, p300 K96, K226 Mouse K96, K222 p300 K352 Human K352 CBP K274 Human K274 MOF K305 Human K305 PCAF K122, 123, 310, 314, K315 Human K122, 123, 310p300 NA Mouse NA p300 K378 Mouse K377 SIRT3 K70, K71 Human K70, K71 p300 SIRT2 K14, K20 Human K14, K20 p300, PCAF SIRT1 K495, K534 Human K495, K534 p300, PCAF SIRT1 K909 Mouse K921 TIP60 K29 Human K29 p300 K179, K182, K250, K335, K4Human K179, K182, K250, K335, K480, SIRT3 K10, K11, K12, K19, K21 Human K10, K11, K12, K19, K21 HDAC4 K160, K188, K259, K366, K7Human K160, K188, K259, K366, K749, SIRT1 K297, K305, K307, K171, K4 Human K297, K305, K3CBP, p300 HDAC4 K150 Human K150 K274 Human K274 MOF NA Human NA SIRT2 K136 Mouse K136 SIRT1 K1092, K1095, K1116, K111Mouse K1080, K1082, p300 K2150, K2156, K2157, K216Human K2150, K2156, p300 K1691, K1730 Mouse K1692, K1731 p300 HDAC1 K251, K253, K254 Human K251, K253, K254 SIRT1 K13, K20 Human K13, K20 SIRT1 K470, K796 Human K470, K796 SIRT1, SIRT2 K27, K29 Human K27, K29 CBP, p300 K340, K383, K410 Human K340, K383, K4 CBP, p300 SIRT2 K539, K542 Human K539, K542 HDAC6 K251 Human K251 NA Human NA ARD1 K129 Human K129 CBP HDAC6 K250 Human K250 PCAF K19 Human K19 K29, K128, K430, K449, K80Human K22, K121, K42CBP, p300 HDAC3 K162, K607 Mouse K162, K606 TIP60 K37 Human K37 K33 Human K33 NA Human NA HDAC1 K274 Human K274 MOF SIRT1 K327, K357 Human K327, K357 TIP60 SIRT1 K385 Human K385 CBP, PCAF HDAC4 K243, K253 Human K243, K253 CBP, p300 K449 Mouse K464 p300 SIRT1 K99, K128 Human K99, K128 p300 K104 Human K104 NA Mouse NA GCN5 NA Human NA HDAC3 K68, K71 Human K68, K71 p300 SIRT3 K47 Human K47 PCAF HDAC6, SIRT2 K32, K36, K37, K51, K52, K5Human K32, K36, K37, p300 K1249 Human K1249 K268, K293 Human K268, K293 SIRT1 K105, K106 Human K105, K106 HDAC8 K274 Human K274 MOF SIRT1 K220 Human K220 PCAF K239, K241, K257, K259 Mouse K235, K237, K2p300 K47 Human K47 HDAC6, SIRT2 K549 Human K549 SIRT6 K161, K163 Human K161, K163 TIP60 K354 Human K354 p300 K335 Human K293 p300 K53 Human K53 CBP, p300 HDAC6 K207 Human K207 SIRT2 K129 Human K129 SIRT1 K65 Human K65 SIRT1 K259 Human K259 p300 SIRT1 NA Human NA CBP SIRT1 K5 Human K5 SIRT2 K195 Human K195 CBP SIRT1 K173 Human K150 CBP K280 Human K280 TAU K104 Human K104 HDAC6, SIRT2 K40 Mouse K40 TAT1 K757 Human K757 p300 K432 Human K432 SIRT1 K263, K268 Mouse K260, K265 SIRT3 NA Human NA p300 K48 Human K48 SIRT2 K540, K546, K554 Human K540, K546, K5 PCAF SIRT2 K83, K84, K87 Human K83, K84, K87 SIRT1 K259, K353 Human K259, K353 p300 HDAC6 NA Human NA SIRT1 NA Human NA CBP SIRT1 K338, K339 Human K338, K339 PCAF K538 Human K538 SIRT1 K433 Human K433 p300 K112, K215 Human K112, K215 MOF SIRT1 NA Human NA CBP SIRT1 K92, K166 Human K92, K166 K226, K275 Human K226, K275 SIRT1 K435 Human K373 CBP SIRT7 K1838, K1859, K1873, K188Human K1838, K1859, CBP, p300 K162 Mouse K139 SIRT3 K82, K125 Human K82, K125 K183 Human K183 p300 K373 Human K372 p300, PCAF NA Human NA p300 SIRT1 NA Rat NA SIRT1 NA Human NA K926, K931 Human K926, K931 SIRT3 K254 Human K254 PCAF HDAC5 K152 Human K152 p300 K3, K7, K8, K12, K28, K29, KHuman K2, K6, K7, K11, K27, K28, K29, K42, K43, K179 K321 Human K321 ACAT1 SIRT3 K202 Human K202 ACAT1 SIRT3 K73, K76 Human K73, K76 TIP60 K75 Mouse K75 CBP, p300 HDAC5 K225, K257, K264 Human K216, K248, K2 NAT8, NAT8B K157, K159 Human K157, K159 p300 HDAC3 NA Human NA CBP NA Human NA p300 K80, K118, K208, K298, K52 Human K80, K118, K20p300 K175, K362 Human K175, K362 SIRT1, SIRT2 K33 Human K33 GCN5 K491 Human K491 K39, K78 Human K39, K78 p300 K403 Human K403 KAT9 SIRT2 K668 Human K668 CBP SIRT2 K327 Human K327 TIP60 K845, K847, K871, K892 Human K845, K847, K871, K892 HDAC6 K13, K14, K77, K80 Human K13, K14, K77, CBP, p300 K55, K88, K90, K177 Human K55, K88, K90, K177 SIRT1 K487 Human K487 SIRT1, SIRT5 K76, K294 Human K76, K294 ACAT2, DLAT HDAC4 K27 Human K27 K917 Human K917 SIRT3 K102 Mouse K102 SIRT1 K69, K352, K381 Human K69, K340, K369 SIRT7 K222 Human K222 HDAC6 K250 Human K250 SIRT2 K353 Human K353 p300 K120, K148, K187, K189 Human K120, K148, K187, K189 HDAC3, SIRT1 NA Human NA HDAC3 K146, K187 Human K146, K187 CBP K353 Human K353 PCAF SIRT2 K136 Human K136 CBP SIRT1 K217 Human K217 K329, K451 Mouse K328, K450 GCN5 K56 Human K56 SIRT3 K475, K482, K789, K825, K1Human K475, K482, K789, K825, K1253SIRT1 K6, K48 Human K6, K48 NA Human NA SIRT1 K145, K192 Human K145, K192 CBP HDAC6 NA Human NA p300 SIRT1 K552 Mouse K549 SIRT2 K121, K198 Human K121, K198 p300 SIRT1 K83, K95, K226, K247, K263 Human K83, K95, K226, K247, K263 K49, K51 Human K49, K51 CBP, p300 SIRT1 K1130, K1133 Human K1130, K1133 CBP, p300 SIRT1 K159, K185, K404 Human K159, K185, K404 SIRT3 NA Human NA HDAC6 K348 Human K348 PCAF NA Human NA PCAF SIRT1 K507 Human K507 SIRT3 K451 Mouse K451 SIRT3 K277 Human K277 HAT1 K439 Human K439 PCAF SIRT1 K266, K377, K469, K770 Human K266, K377, K469, K770 SIRT1 K69, K81, K99 Human K69, K81, K99 p300 SIRT1 K53 Human K53 SIRT1 K81 Human K81 p300 HDAC3, SIRT1 K430, K437 Human K430, K437 p300 SIRT1 K71 Human K71 SIRT1 K438, K443 Human K438, K443 PCAF SIRT1 K353 Human K353 HDAC6 K134 Human K134 CBP, p300, TIP60 K152 Human K152 TAT1 NA Human NA CBP, p300 K37 Human K37 SIRT1, SIRT2, SI NA Human NA p300 K37, K142 Human K37, K142 CBP, TIP60 K71 Human K71 SIRT2 K94 Human K94 p300 HDAC10, SIRT4 NA Human NA SIRT1 K1116, K1119, K1125 Human K1116, K1119, K1125 HDAC4, HDAC5 K163 Human K163 HDAC6 K95 Human K95 TIP60 K220 Human K220 KAT9 HDAC3 K174 Human K174 CBP, p300 SIRT1 K647, K650, K653 Human K647, K650, K6 CBP, p300 HDAC3, SIRT1 K45, K72, K91 Human K45, K72, K91 SIRT1 K379 Mouse K379 K81 Human K81 p300 HDAC1 K45, K46 Human K45, K46 SIRT3 NA Human NA PCAF K87, K124, K161, K198, K23Human K87, K124, K16CBP SIRT1 NA Human NA SIRT1 K150 Human K150 CBP HDAC1, HDAC3 K15 Human K15 SIRT3 K43, K178 Human K43, K178 p300 K43, K52, K138, K178 Human K43, K52, K138, K178 SIRT2 K52 Human K52 HDAC6 K52, K138, K141, K178 Human K52, K138, K14PCAF K228, K232 Mouse K225, K229 CBP, p300 K909 Human K909 HDAC6 K433 Human K433 SIRT6 K215 Human K215 TIP60 K32 Human K32 SIRT2 K109 Human K109 p300 SIRT1 K12, K25 Human K12, K25 SIRT7 NA Human NA SIRT1 K228, K232 Mouse K227, K231 NA Human NA K11, K14 Human K11, K14 p300 NA Human NA SIRT1 K298, K302 Human K298, K302 GCN5 K279 Human K279 K305 Human K305 SIRT2 K219 Mouse K217 K307, K312 Human K307, K312 CBP, p300 HDAC4 K432, K433, K436 Human K432, K433, K4 MOF K109, K122, K124, K147, K1Human K109, K122, K1p300 SIRT1 K418 Human K418 GCN5 SIRT1 K63, K422, K440, K603, K61 Human K63, K422, K44CBP, p300 K27 Human K27 SIRT1 NA Human NA SIRT1 K370, K372, K373, K381, K3Human K370, K372, K3CBP, p300 K196, K200, K203, K206 Human K196, K200, K2CBP, p300 HDAC1, HDAC2 K147 Human K147 SIRT2 K11, K43, K44, K47 Human K11, K43, K44, CBP, p300 NA Mouse NA SIRT1 K242, K259, K290, K569 Human K242, K259, K290, K569 SIRT1, SIRT7 K77 Human K77 ARD1 K219 Human K225 K45, K46 Human K45, K46 GCN5, PCAF NA Human NA K183 Mouse K182 SIRT1 K141, K143 Human K141, K143 SIRT1 K244 Human K244 PCAF SIRT1 K110 Human K110 p300 HDAC1, HDAC2 K880, K886, K896 Human K880, K886, K8 p300 HDAC2 K81 Human K81 SIRT1 K1479 Human K1479 SIRT1 K182, K185 Human K182, K185 p300 SIRT1 K65 Human K65 p300 K518 Human K518 HDAC1, HDAC2 K56 Human K56 PCAF HDAC6 K187 Human K187 p300 K890 Human K890 HDAC1 K21 Human K21 K413 Human K413 SIRT3 K289, K291, K296 Mouse K291, K293, K2 GCN5 SIRT1 K209, K214, K230, K232 Human K209, K214, K2PCAF NA Mouse NA K247 Mouse K247 CBP, p300 HDAC6, HDAC1 K1121 Human K1121 SIRT7 K413 Human K413 SIRT1 K518 Human K518 p300 NA Mouse NA GCN5 K18, K137, K600 Human K18, K137, K60 CBP SIRT7 NA Human NA SIRT7 K831, K837, K840, K885 Human K813, K819, K822, K868 SIRT2 K122 Mouse K57 SIRT1 K414 Human K414 CBP SIRT2 K29, K771, K781 Human K29, K771, K78 p300 K8, K18 Human K8, K18 K364 Human K364 TIP60 K163 Human K163 GCN5, PCAF K163 Human K163 GCN5, PCAF HDAC6 K119 Human K119 CBP K75, K125 Human K75, K125 ARD1 K238, K377 Mouse K230, K369 SIRT7 K405 Human K405 ARD1 K165, K176 Human K165, K176 CLOCK K305 Human K305 PCAF K433 Human K433 p300 K239, K405 Human K141, K307 HDAC3 K339 Human K339 GCN5, PCAF NA Human NA K1626, K1628 Human K1626, K1628 CBP HDAC2 K126 Human K126 SIRT2 K479 Human K479 HDAC1 K119 Human K119 CBP K333 Human K333 TIP60 NA Human K141 CBP K5, K7, K9, K404, K426, K43 Human K5, K7, K9, K40CBP K75, K476, K582 Human K75, K476, K58 CBP NA Mouse NA p300 SIRT1 NA Human NA SIRT3 K190, K192, K262, K274, K2Human K190, K192, K2CBP, p300 SIRT2, SIRT3 K168 Human K168 K376, K390, K440, K448 Human K376, K390, K440, K448 SIRT1 K125 Human K125 TIP60 HDAC1 K685 Human K685 SIRT1 NA Human NA SIRT2 K120, K382 Human K120, K382 MOZ K439 Mouse K424 CBP SIRT1 K314 Human K314 CBP, p300 SIRT1 Pubmed.ID 9288740 9655350 9707565 9744860 9744860 9809067 9809067 9859997 9891054 10207070 10207073 10490106 11250901 11509556 10619020 10656693 11533489 10675335 10753885 10753971 10779504 10801418 11568182 10882110 10944526 10970860 11046145 11073948 11099047 11118214 11807779 12384494 14506733 14982997 15123636 15126506 15916966 11154691 11259590 15937340 11279135 11369851 15965232 11430825 11433299 11486036 11498590 11498590 11509661 11672523 11739381 11804596 11812829 15987677 11864601 11973335 11994312 12024216 12374802 12402037 12408818 12419806 16141325 12456660 12464182 12499368 12595525 16207715 12620231 12640139 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In vivo acetylation identified at lysine 70 of human lens alphaA-crystallin. Acetylation and modulation of erythroid Krüppel-like factor (EKLF) activity by interaction with histo DNA damage activates p53 through a phosphorylation-acetylation cascade. DNA damage activates p53 through a phosphorylation-acetylation cascade. Acetylation of HMG I(Y) by CBP turns off IFN beta expression by disrupting the enhanceosome. Acetylation of HMG I(Y) by CBP turns off IFN beta expression by disrupting the enhanceosome. Regulation of activity of the transcription factor GATA-1 by acetylation. p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Specific acetylation of chromosomal protein HMG-17 by PCAF alters its interaction with nucleosom CREB-Binding protein acetylates hematopoietic transcription factor GATA-1 at functionally importa Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an Acetylation of TAF(I)68, a subunit of TIF-IB/SL1, activates RNA polymerase I transcription. Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transc Acetylation of MyoD directed by PCAF is necessary for the execution of the muscle program. c-Myb acetylation at the carboxyl-terminal conserved domain by transcriptional co-activator p300. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Regulation of E2F1 activity by acetylation. E2F family members are differentially regulated by reversible acetylation. Acetylation of novel sites in the nucleosomal binding domain of chromosomal protein HMG-14 by p p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen Acetylation of importin-alpha nuclear import factors by CBP/p300. Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/ Acetylation regulates transcription factor activity at multiple levels. CREB-binding protein/p300 activates MyoD by acetylation. Acetylation of GATA-3 affects T-cell survival and homing to secondary lymphoid organs. Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompa Increased affinity of c-Myb for CREB-binding protein (CBP) after CBP-induced acetylation. Deacetylation of p53 modulates its effect on cell growth and apoptosis. P/CAF-mediated acetylation regulates the function of the basic helix-loop-helix transcription factor Modulation of HMG-N2 binding to chromatin by butyrate-induced acetylation in human colon aden DNA damage-induced translocation of the Werner helicase is regulated by acetylation. Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative reg Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Specific role for p300/CREB-binding protein-associated factor activity in E2F1 stabilization in respon FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid recepto Stimulation of NF-E2 DNA binding by CREB-binding protein (CBP)-mediated acetylation. Site-specific acetylation by p300 or CREB binding protein regulates erythroid Krüppel-like factor tra Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock pr Direct acetylation of the alpha hinge region by p300 regulates transactivation an In vivo carbamylation and acetylation of water-soluble human lens alphaB-crystallin lysine 92. p300 regulates p63 transcriptional activity. Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactiv Acetylation control of the retinoblastoma tumour-suppressor protein. Regulation of transcription factor YY1 by acetylation and deacetylation. Coordination of a transcriptional switch by HMGI(Y) acetylation. Coordination of a transcriptional switch by HMGI(Y) acetylation. Acetylation of nuclear -interacting protein RIP140 regulates binding of the transc hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Enhancement of nuclear factor-kappa B acetylation by coactivator p300 and HIV-1 Tat proteins. DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target gen Transcription factor Sp3 is regulated by acetylation. p300/CBP-associated factor drives DEK into interchromatin granule clusters. Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription Acetylation of beta-catenin by CREB-binding protein (CBP). Tip60 and histone deacetylase 1 regulate activity through changes to the acetyla HDAC6 is a microtubule-associated deacetylase. Acetylation of interferon regulatory factor-7 by p300/CREB-binding protein (CBP)-associated factor Acetylation inactivates the transcriptional repressor BCL6. Control of Smad7 stability by competition between acetylation and ubiquitination. Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. DNA-dependent acetylation of p53 by the transcription coactivator p300. Acetylation of cAMP-responsive element-binding protein (CREB) by CREB-binding protein enhances Sumoylation and acetylation play opposite roles in the transactivation of PLAG1 and PLAGL2. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors. Interferon regulatory factor-2 regulates cell growth through its acetylation. Functional interplay between CBP and PCAF in acetylation and regulation of transcription factor KLF Mechanisms of P/CAF auto-acetylation. Acetylation-mediated transcriptional activation of the ETS protein ER81 by p300, P/CAF, and HER2/ P300/CBP acts as a coactivator to cartilage homeoprotein-1 (Cart1), paired-like homeoprotein, thro Sumoylation and acetylation play opposite roles in the transactivation of PLAG1 and PLAGL2. Transcription factor IIB acetylates itself to regulate transcription. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. Positive and negative regulation of the cardiovascular transcription factor KLF5 by p300 and the onc Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone Acetylation of the BETA2 transcription factor by p300-associated factor is important in insulin gene Acetylation and alternative splicing regulate ZNF76-mediated transcription. AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues. Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Functional role of NF-IL6beta and its sumoylation and acetylation modifications in promoter activat Functional regulation of GATA-2 by acetylation. Regulation of the p300 HAT domain via a novel activation loop. In vitro acetylation of HMGB-1 and -2 proteins by CBP: the role of the acidic tail. In vitro acetylation of HMGB-1 and -2 proteins by CBP: the role of the acidic tail. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Acetylation regulates the differentiation-specific functions of the . Acetylation of beta-catenin by p300 regulates beta-catenin-Tcf4 interaction. Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubi Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. Acetylation of the human DNA glycosylase NEIL2 and inhibition of its activity. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase act Site-specific acetylation of the fetal globin activator NF-E4 prevents its ubiquitination and regulates Regulation of human SRY subcellular distribution by its acetylation/deacetylation. Stability of the hepatocyte nuclear factor 6 transcription factor requires acetylation by the CREB-bin The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60. Phosphorylation of blocks its acetylation and regulates estrogen sensitivity Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein- Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Myocyte enhancer factor 2 acetylation by p300 enhances its DNA binding activity, transcriptional ac Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcriptio NF-kappaB RelA phosphorylation regulates RelA acetylation. Bone morphogenetic protein-2 stimulates Runx2 acetylation. Stimulation of GCMa transcriptional activity by cyclic AMP/protein kinase A signaling is attributed to Protein acetylation regulates both PU.1 transactivation and Ig kappa 3' enhancer activity. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of Smad3 is acetylated by p300/CBP to regulate its transactivation activity. Regulation of SIRT 1 mediated NAD dependent deacetylation: a novel role for the multifunctional e p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase do Regulation of Kruppel-like factor 6 tumor suppressor activity by acetylation. Dual regulation of c-Myc by p300 via acetylation-dependent control of Myc protein turnover and co SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. SF-1 (nuclear receptor 5A1) activity is activated by cyclic AMP via p300-mediated recruitment to act Acetylation by p300 regulates nuclear localization and function of the transcriptional corepressor C DNA-damage-responsive acetylation of pRb regulates binding to E2F-1. Acetylation of human 8-oxoguanine-DNA glycosylase by p300 and its role in 8-oxoguanine repair in Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene trans Acetylation of Stat1 modulates NF-kappaB activity. Acetylation of estrogen receptor alpha by p300 at lysines 266 and 268 enhances the deoxyribonucle c-Abl acetylation by histone acetyltransferases regulates its nuclear-cytoplasmic localization. Stat3 activation of NF-{kappa}B p100 processing involves CBP/p300-mediated acetylation. HDAC1 acetylation is linked to progressive modulation of steroid receptor-induced gene transcriptio Deacetylase inhibition promotes the generation and function of regulatory T cells. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetas A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. PCAF modulates PTEN activity. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Acetylation and MAPK phosphorylation cooperate to regulate the degradation of active GATA-1. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Smad3 is acetylated by p300/CBP to regulate its transactivation activity. Acetylation of mouse p53 at lysine 317 negatively regulates p53 apoptotic activities after DNA dam HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells. Acetylation regulates WRN catalytic activities and affects base excision DNA repair. The DNA binding activities of Smad2 and Smad3 are regulated by coactivator-mediated acetylation. The DNA binding activities of Smad2 and Smad3 are regulated by coactivator-mediated acetylation. CCAAT/enhancer-binding protein (C/EBP) beta is acetylated at multiple lysines: acetylation of C/EBP Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3'-end processing. Multiple histone deacetylases and the CREB-binding protein regulate pre-mRNA 3'-end processing. Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosi Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Max is acetylated by p300 at several nuclear localization residues. Regulation of autophagy by the p300 acetyltransferase. Regulation of autophagy by the p300 acetyltransferase. Regulation of autophagy by the p300 acetyltransferase. An acetylation site in the middle domain of Hsp90 regulates chaperone function. Regulation of autophagy by the p300 acetyltransferase. hSirT1-dependent regulation of the PCAF-E2F1-p73 apoptotic pathway in response to DNA damage A repeat domain in the Notch co-activator MAML1 is important for the p300-mediated acet Acetylation of histone deacetylase 6 by p300 attenuates its deacetylase activity. SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribo Sumoylation of poly(ADP-ribose) polymerase 1 inhibits its acetylation and restrains transcriptional c Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Acetylation of transition protein 2 (TP2) by KAT3B (p300) alters its DNA condensation property and Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by in A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilizatio Regulation of P-TEFb elongation complex activity by CDK9 acetylation. Multiple roles for acetylation in the interaction of p300 HAT with ATF-2. SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Tip60 histone acetyltransferase acts as a negative regulator of Notch1 signaling by means of acetyla HDAC6 modulates cell motility by altering the acetylation level of cortactin. Orphan receptor TR3 attenuates the p300-induced acetylation of -alpha. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide sy Transforming growth factor-beta regulates DNA binding activity of transcription factor Fli1 by p300/ The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphoryla Acetylation-dependent signal transduction for type I interferon receptor. DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Valproic acid induces functional heat-shock protein 70 via Class I histone deacetylase inhibition in c An acetylation switch in p53 mediates holo-TFIID recruitment. Lysine acetylation regulates Bruton's tyrosine kinase in B cell activation. The orphan nuclear receptor Rev-erbbeta recruits Tip60 and HDAC1 to regulate apolipoprotein CIII Histone acetyltransferases interact with and acetylate p70 ribosomal S6 kinases in vitro and in vivo. CLOCK-mediated acetylation of BMAL1 controls circadian function. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardio Identification of p300-targeted acetylated residues in GATA4 during hypertrophic responses in card Methylation of p53 by Set7/9 mediates p53 acetylation and activity in vivo. Identification of lysines 36 and 37 of PARP-2 as targets for acetylation and auto-ADP-ribosylation. Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation. HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation. Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and y Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis. PTEN acetylation modulates its interaction with PDZ domain. Deacetylation of cortactin by SIRT1 promotes cell migration. The SIRT2 deacetylase regulates autoacetylation of p300. Acetylation-dependent interaction of SATB1 and CtBP1 mediates transcriptional repression by SATB Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocortic Histone acetyltransferases interact with and acetylate p70 ribosomal S6 kinases in vitro and in vivo. Phosphorylation of Fli1 at threonine 312 by protein kinase C delta promotes its interaction with p30 Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. A role of DNA-PK for the metabolic gene regulation in response to insulin. Lysine 88 acetylation negatively regulates ornithine carbamoyltransferase activity in response to nu Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle. Acetylation targets mutant huntingtin to autophagosomes for degradation. Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells. Target gene specificity of USF-1 is directed via p38-mediated phosphorylation-dependent acetylatio Acetylation of Dna2 endonuclease/helicase and flap endonuclease 1 by p300 promotes DNA stabilit BubR1 acetylation at prometaphase is required for modulating APC/C activity and timing of mitosis Degradation of cyclin A is regulated by acetylation. GCN5-mediated transcriptional control of the metabolic coactivator PGC-1beta through lysine acety Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin Reversible acetylation of the chromatin remodelling complex NoRC is required for non-coding RNA- Acetylated NPM1 localizes in the nucleoplasm and regulates transcriptional activation of genes imp Acetylation of sox2 induces its nuclear export in embryonic stem cells. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Acetylation of RTN-1C regulates the induction of ER stress by the inhibition of HDAC activity in neur The transcriptional co-activator PCAF regulates cdk2 activity. Residues K128, 132, and 134 in the -alpha are essential for receptor acety Arrest defective-1 controls tumor cell behavior by acetylating myosin light chain kinase. SIRT1 regulates autoacetylation and histone acetyltransferase activity of TIP60. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in m NAD+-dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of t HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autoph Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalli Functional interplay between acetylation and methylation of the RelA subunit of NF-kappaB. Regulation of cellular metabolism by protein lysine acetylation. SIRT1 regulates oxidant- and cigarette smoke-induced eNOS acetylation in endothelial cells: Role of Regulation of cellular metabolism by protein lysine acetylation. Treatment with panobinostat induces glucose-regulated protein 78 acetylation and endoplasmic re Regulation of Nur77 protein turnover through acetylation and deacetylation induced by p300 and H Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Regulation of cellular metabolism by protein lysine acetylation. Deacetylation of FoxO by Sirt1 Plays an Essential Role in Mediating Starvation-Induced Autophagy in DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiq SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Acetylation of lysine 564 adjacent to the C-terminal binding protein-binding motif in EVI1 is crucial f Acetylation regulates cyclophilin A catalysis, immunosuppression and HIV isomerization. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under calo Acetylation of WRN protein regulates its stability by inhibiting ubiquitination. An acetylation switch modulates the transcriptional activity of estrogen-related receptor alpha. Arrest defective 1 autoacetylation is a critical step in its ability to stimulate cancer cell proliferation Acetylation of protein determines selective function independent of ligand act Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator S6K1 is acetylated at lysine 516 in response to growth factor stimulation. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Acetylation-dependent oncogenic activity of metastasis-associated protein 1 co-regulator. RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast diff Pleiotropic effects of p300-mediated acetylation on p68 and p72 RNA helicase. Pleiotropic effects of p300-mediated acetylation on p68 and p72 RNA helicase. HDAC-mediated deacetylation of NF-κB is critical for Schwann cell myelination. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose h HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer. SIRT1 Regulates Thyroid-Stimulating Hormone Release by Enhancing PIP5Kgamma Activity through SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Cell cycle-dependent acetylation of Rb2/p130 in NIH3T3 cells. p300-mediated acetylation stabilizes the Th-inducing POK factor. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. Acetylation directs survivin nuclear localization to repress STAT3 oncogenic activity. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac myocyte proliferatio Acetylation of tau inhibits its degradation and contributes to tauopathy. Acetylation of Rb by PCAF is required for nuclear localization and differentiation. Acetylation modulates prolactin receptor dimerization. The major alpha-tubulin K40 acetyltransferase alphaTAT1 promotes rapid ciliogenesis and efficient SIRT2 regulates NF-κB dependent gene expression through deacetylation of p65 Lys310. Acetylation of EGF receptor contributes to tumor cell resistance to histone deacetylase inhibitors. Sirt1 deacetylates c-Myc and promotes c-Myc/Max association. Pancreatic β-cell prosurvival effects of the incretin hormones involve post-translational modificatio Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degrad SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Acetylation and phosphorylation of SRSF2 control cell fate decision in response to cisplatin. Role of Pax3 acetylation in the regulation of Hes1 and Neurog2. Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in res Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age- Cyclin-dependent kinase 5 phosphorylates mammalian HMGB1 protein only if acetylated. Nε-lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 Histone acetyltransferase p300 acetylates Pax5 and strongly enhances Pax5-mediated transcription Regulation of the oncoprotein KLF8 by a switch between acetylation and sumoylation. Acetylation-dependent regulation of mitochondrial ALDH2 activation by SIRT3 mediates acute etha The acetylation of tau inhibits its function and promotes pathological tau aggregation. Acetylation of a conserved lysine residue in the ATP binding pocket of p38 augments its kinase activ Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Acetylation of lysine 120 of p53 endows DNA-binding specificity at effective physiological salt conce Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy Dynamic modification of the ETS transcription factor PEA3 by sumoylation and p300-mediated acet Dysregulation of upstream binding factor-1 acetylation at K352 is linked to impaired ribosomal DNA Regulation of the histone acetyltransferase activity of hMOF via autoacetylation of Lys274. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediate Regulation of NF-κB activity by competition between RelA acetylation and ubiquitination. PRC2 directly methylates GATA4 and represses its transcriptional activity. SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ub The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tum The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tum Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl. p300-Dependent ATF5 acetylation is essential for Egr-1 gene activation and cell proliferation and su Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. HDAC4 protein regulates HIF1α protein lysine acetylation and cancer cell response to hypoxia. SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities. The acetylation of transcription factor HBP1 by p300/CBP enhances p16INK4A expression. Acetylation of Prrp K150 regulates the subcellular localization. MYST protein acetyltransferase activity requires active site lysine autoacetylation. Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy ex Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Cr Multiple site acetylation of Rictor stimulates mammalian target of rapamycin complex 2 (mTORC2)- Ubiquitination of Notch1 is regulated by MAML1-mediated p300 acetylation of Notch1. Acetylation controls Notch3 stability and function in T-cell leukemia. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylatio Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB trans Acetylation negatively regulates glycogen phosphorylase by recruiting protein phosphatase 1. Acetylation of sphingosine kinase 1 regulates cell growth and cell-cycle progression. Regulation of inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) by reversible lysine acetylation. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and H Helical repeat structure of apoptosis inhibitor 5 reveals protein-protein interaction modules. Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prosta Histone deacetylase 6 (HDAC6) deacetylates survivin for its nuclear export in breast cancer. BRCA2 fine-tunes the spindle assembly checkpoint through reinforcement of BubR1 acetylation. Reversible lysine acetylation regulates activity of human glycine N-acyltransferase-like 2 (hGLYATL2 A redox-regulated SUMO/acetylation switch of HIPK2 controls the survival threshold to oxidative st GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. An acetylation switch regulates SUMO-dependent protein interaction networks. An acetylation switch regulates SUMO-dependent protein interaction networks. A RUNX2-HDAC1 co-repressor complex regulates rRNA gene expression by modulating UBF acetylat SIRT1 negatively regulates the activities, functions, and protein levels of hMOF and TIP60. SIRT1 negatively regulates the activities, functions, and protein levels of hMOF and TIP60. A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. is acetylated by transcription coactivator CBP/p300. SIRT1-mediated deacetylation of MeCP2 contributes to BDNF expression. Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein I Regulation of RAS oncogenicity by acetylation. CITED2 links hormonal signaling to PGC-1α acetylation in the regulation of gluconeogenesis. Aurora B is regulated by acetylation/deacetylation during mitosis in cells. Acetylation-dependent regulation of Skp2 function. Acetylation regulates subcellular localization of eukaryotic translation initiation factor 5A (eIF5A). Modulation of histone deacetylase 6 (HDAC6) nuclear import and tubulin deacetylase activity throu FANCJ/BACH1 acetylation at lysine 1249 regulates the DNA damage response. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Autoacetylation of the MYST lysine acetyltransferase MOF protein. EB1 acetylation by P300/CBP-associated factor (PCAF) ensures accurate kinetochore-microtubule in Acetylation of myocardin is required for the activation of cardiac and smooth muscle genes. The role of acetylation in the subcellular localization of an oncogenic isoform of translation factor e The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis Stabilization of p21 (Cip1/WAF1) following Tip60-dependent acetylation is required for p21-mediat Glucose-induced β-catenin acetylation enhances Wnt signaling in cancer. p300-mediated acetylation of TRF2 is required for maintaining functional telomeres. Reversible acetylation regulates salt-inducible kinase (SIK2) and its function in autophagy. Glucose and SIRT2 reciprocally mediate the regulation of keratin 8 by lysine acetylation. A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SA Ubc9 acetylation modulates distinct SUMO target modification and hypoxia response. -induced acetylation of Foxa2 regulates hepatic lipid metabolism. The acetylase/deacetylase couple CREB-binding protein/Sirtuin 1 controls hypoxia-inducible factor Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic ca Site-specific acetylation of the proteasome activator REGγ directs its heptameric structure and func Acetylation of human TCF4 (TCF7L2) proteins attenuates inhibition by the HBP1 repressor and indu The microtubule-associated tau protein has intrinsic acetyltransferase activity. HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS. αTAT1 is the major α-tubulin acetyltransferase in mice. Gli2 acetylation at lysine 757 regulates hedgehog-dependent transcriptional output by preventing i SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Quantification of mitochondrial acetylation dynamics highlights prominent sites of metabolic regula p300/CBP acetyl transferases interact with and acetylate the nucleotide excision repair factor XPG. SIRT2 directs the replication stress response through CDK9 deacetylation. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Histone deacetylase SIRT1 modulates and deacetylates DNA base excision repair enzyme thymine D Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and SIRT1 deacetylates RFX5 and antagonizes repression of collagen type I (COL1A2) transcription in sm Incretin-stimulated interaction between β-cell Kv1.5 and Kvβ2 channel proteins involves acetylation PCAF impairs endometrial receptivity and embryo implantation by down-regulating β3-integrin exp Metastasis-associated protein 1 is an integral component of the circadian molecular machinery. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity an hMOF acetylation of DBC1/CCAR2 prevents binding and inhibition of SirT1. Incretin-stimulated interaction between β-cell Kv1.5 and Kvβ2 channel proteins involves acetylation Acetylation of lysine 92 improves the chaperone and anti-apoptotic activities of human αB-crystalli SIRT1 deacetylates FOXA2 and is critical for Pdx1 transcription and β-cell formation. Repression of RNA polymerase I upon stress is caused by inhibition of RNA-dependent deacetylatio Acetylation of RNA polymerase II regulates growth-factor-induced gene transcription in mammalian SIRT3 deacetylates ATP synthase F1 complex proteins in response to nutrient- and exercise-induced Acetylation of cyclophilin A is required for its secretion and vascular cell activation. Acetylation at lysine 183 of by p300 accelerates DNA binding kinetics and tra HDAC6 mediates the acetylation of TRIM50. Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetyl Sirt1 promotes axonogenesis by deacetylation of Akt and inactivation of GSK3. The E3 ubiquitin ligase Itch regulates tumor suppressor protein RASSF5/NORE1 stability in an acety SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Glyceraldehyde-3-phosphate dehydrogenase is activated by lysine 254 acetylation in response to gl P300 binds to and acetylates MTA2 to promote colorectal cancer cells growth. JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvat Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvat Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like br Regulation of acetylation of histone deacetylase 2 by p300/CBP-associated factor/histone deacetyla Post-translational regulation of CD133 by ATase1/ATase2-mediated lysine acetylation. Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis. Caspase-14 suppresses GCM1 acetylation and inhibits placental cell differentiation. TGF-β induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic n Interplay of acetyltransferase EP300 and the proteasome system in regulating heat shock transcript Regulation of the mitogen-activated protein kinase kinase (MEK)-1 by NAD(+)-dependent deacetyla Acetylation of cyclin-dependent kinase 5 is mediated by GCN5. MARCH5-mediated quality control on acetylated Mfn1 facilitates mitochondrial homeostasis and ce Sublytic C5b-9 triggers glomerular mesangial cell apoptosis via XAF1 gene activation mediated by p3 Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. CBP and p300 acetylate PCNA to link its degradation with nucleotide excision repair synthesis. High-mobility group box 1 is a novel deacetylation target of Sirtuin1. Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell deat Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Significant enhancement of hPrx1 chaperone activity through lysine acetylation. Sirtuin 3 interacts with Lon protease and regulates its acetylation status. SIRT1-mediated deacetylation of CRABPII regulates cellular retinoic acid signaling and modulates em A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function. MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged Deacetylation of the mitotic checkpoint protein BubR1 at lysine 250 by SIRT2 and subsequent effec De-acetylation and degradation of HSPA5 is critical for E1A metastasis suppression in breast cancer Regulation of histone acetyltransferase TIP60 function by histone deacetylase 3. DNA damage induced MutS homologue hMSH4 acetylation. Acetylation of snail modulates the cytokinome of cancer cells to enhance the recruitment of macro NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells. Combinatorial regulation of a signal-dependent activator by phosphorylation and acetylation. A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. PCAF improves glucose homeostasis by suppressing the gluconeogenic activity of PGC-1α. Prolonged fasting identifies 10 as a Sirtuin 3 substrate: elucidating a new mecha SIRT1 deacetylates TopBP1 and modulates intra-S-phase checkpoint and DNA replication origin firin Ubiquitin acetylation inhibits polyubiquitin chain elongation. SIRT1 negatively regulates the protein stability of HIPK2. An acetylation switch controls TDP-43 function and aggregation propensity. Histone deacetylase sirtuin 1 deacetylates IRF1 protein and programs dendritic cells to control Th17 Acetylation of TUG protein promotes the accumulation of GLUT4 glucose transporters in an insulin- Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation. Acetylation of the RhoA GEF Net1A controls its subcellular localization and activity. Deacetylation of nuclear LC3 drives autophagy initiation under starvation. NAD(+)-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1. SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and p LC3B-II deacetylation by histone deacetylase 6 is involved in serum-starvation-induced autophagic d PCAF-primed EZH2 acetylation regulates its stability and promotes lung adenocarcinoma progressio Reversible acetylation of Lin28 mediated by PCAF and SIRT1. SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain acyl-CoA de SIRT3 mediates multi-tissue coupling for metabolic fuel switching. The acetyltransferase HAT1 moderates the NF-κB response by regulating the transcription factor PL MPP8 and SIRT1 crosstalk in E-cadherin gene silencing and epithelial-mesenchymal transition. KAP1 Deacetylation by SIRT1 Promotes Non-Homologous End-Joining Repair. SIRT1 deacetylates RORγt and enhances Th17 cell generation. SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Functio Acetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular canc Acetylation of Beclin 1 inhibits autophagosome maturation and promotes tumour growth. Acetylation at lysine 71 inactivates superoxide dismutase 1 and sensitizes cancer cells to genotoxic Cooperative Action of Cdk1/cyclin B and SIRT1 Is Required for Mitotic Repression of rRNA Synthesis Deacetylation of HSPA5 by HDAC6 leads to GP78-mediated HSPA5 ubiquitination at K447 and suppr Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation. Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation. Acetylation regulates the stability of glutamate carboxypeptidase II protein in human astrocytes. Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation. p300-mediated acetylation of COMMD1 regulates its stability, and the ubiquitylation and nucleolar Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation. Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation. Acetylation-dependent function of human single-stranded DNA binding protein 1. SIRT1 directly regulates SOX2 to maintain self-renewal and multipotency in bone marrow-derived m Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance. PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition. KAT5-mediated SOX4 acetylation orchestrates chromatin remodeling during myoblast differentiatio Insulin and mTOR Pathway Regulate HDAC3-Mediated Deacetylation and Activation of PGK1. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Post transcriptional control of the epigenetic stem cell regulator PLZF by sirtuin and HDAC deacetyl Acetylation of NDPK-D Regulates Its Subcellular Localization and Cell Survival. Bcl6 middle domain repressor function is required for T follicular helper cell differentiation and util Reciprocal regulation of RORγt acetylation and function by p300 and HDAC1. Sirt3 binds to and deacetylates mitochondrial pyruvate carrier 1 to enhance its activity. PCAF-mediated Akt1 acetylation enhances the proliferation of human glioblastoma cells. The subcellular localization and activity of cortactin is regulated by acetylation and interaction with SIRT1 Interacts with and Deacetylates ATP6V1B2 in Mature Adipocytes. Olig1 Acetylation and Nuclear Export Mediate Oligodendrocyte Development. SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synt Structural and Mechanistic Insights into the Regulation of the Fundamental Rho Regulator RhoGDIα Structural and Mechanistic Insights into the Regulation of the Fundamental Rho Regulator RhoGDIα Structural and Mechanistic Insights into the Regulation of the Fundamental Rho Regulator RhoGDIα Structural and Mechanistic Insights into the Regulation of the Fundamental Rho Regulator RhoGDIα p21 and CK2 interaction-mediated HDAC2 phosphorylation modulates KLF4 acetylation to regulate HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I. SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions. Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation. ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity. SIRT7-dependent deacetylation of the U3-55k protein controls pre-rRNA processing. Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent KLF7 Regulates Satellite Cell Quiescence in Response to Extracellular Signaling. Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arre Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomi Mammalian Sterile 20-like Kinase 1 (Mst1) Enhances the Stability of Forkhead Box P3 (Foxp3) and th Acetylation of C/EBPα inhibits its granulopoietic function. Opposing post-translational modifications regulate Cep76 function to suppress centriole amplificati SIRT2-Mediated Deacetylation and Tetramerization of Pyruvate Kinase Directs Glycolysis and Tumo Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Osterix acetylation at K307 and K312 enhances its transcriptional activity and is required for osteob MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition. Acetylation of Mammalian ADA3 Is Required for Its Functional Roles in Histone Acetylation and Cell Acetylation of Mammalian ADA3 Is Required for Its Functional Roles in Histone Acetylation and Cell Acetylation of FOXM1 is essential for its transactivation and tumor growth stimulation. PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progre Acetylation reduces SOX9 nuclear entry and ACAN gene transactivation in human chondrocytes. Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. Acetylation-Dependent Control of Global Poly(A) RNA Degradation by CBP/p300 and HDAC1/2. SIRT2 deletion enhances KRAS-induced tumorigenesis in vivo by regulating K147 acetylation status. Wnt/β-catenin-dependent acetylation of Pygo2 by CBP/p300 histone acetyltransferase family mem Sirtuin 1 Promotes Deacetylation of Oct4 and¬†Maintenance of Naive Pluripotency. The interaction between acetylation and serine-574 phosphorylation regulates the apoptotic functi ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation. Acetylation of VGLL4 Regulates Hippo-YAP Signaling and Postnatal Cardiac Growth. KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome am Hsp70 acetylation prevents caspase-dependent/independent apoptosis and autophagic cell death i SIRT1 deacetylates the cardiac transcription factor Nkx2.5 and inhibits its transcriptional activity. SIRT1 protects the heart from ER stress-induced cell death through eIF2α deacetylation. Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage. Acetylation Enhances TET2 Function in Protecting against Abnormal DNA Methylation during Oxida Opposing Roles of Acetylation and Phosphorylation in LIFR-Dependent Self-Renewal Growth Signali Sirtuin1-regulated lysine acetylation of p66Shc governs diabetes-induced vascular oxidative stress a Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel. Acetylation-dependent regulation of MDM2 E3 ligase activity dictates its oncogenic function. Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogen Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical mode HDAC6-mediated acetylation of lipid droplet-binding protein CIDEC regulates fat-induced lipid stora Snail acetylation by histone acetyltransferase p300 in lung cancer. HDAC Inhibitor-Induced Mitotic Arrest Is Mediated by Eg5/KIF11 Acetylation. Post-translational modification of HINT1 mediates activation of MITF transcriptional activity in hum SIRT3-Mediated Dimerization of IDH2 Directs Cancer Cell Metabolism and Tumor Growth. Acetylation of Cavin-1 Promotes Lipolysis in White Adipose Tissue. Acetylation of MKL1 by PCAF regulates pro-inflammatory transcription. Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells. Identification of zinc finger transcription factor EGR2 as a novel acetylated protein. Sirtuin 7-dependent deacetylation of DDB1 regulates the expression of nuclear receptor TR4. SIRT1 enzymatically potentiates 1,25-dihydroxyvitamin D3 signaling via deacetyl β-arrestin1-mediated acetylation of Gli1 regulates Hedgehog/Gli signaling and modulates self-renew The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard geno SIRT7 deacetylates DDB1 and suppresses the activity of the CRL4 E3 ligase complexes. Crucial Roles for SIRT2 and AMPA Receptor Acetylation in Synaptic Plasticity and Memory. Obesity and aging diminish sirtuin 1 (SIRT1)-mediated deacetylation of SIRT3, leading to hyperacety Membrane localization of acetylated CNK1 mediates a positive feedback on RAF/ERK signaling. VPS34 Acetylation Controls Its Lipid Kinase Activity and the Initiation of Canonical and Non-canonic VEGF amplifies transcription through ETS1 acetylation to enable angiogenesis. A posttranslational modification cascade involving p38, Tip60, and PRAK mediates oncogene-induce PCAF/GCN5-Mediated Acetylation of RPA1 Promotes Nucleotide Excision Repair. UV-Induced RPA1 Acetylation Promotes Nucleotide Excision Repair. CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of S ARD1-mediated aurora kinase A acetylation promotes cell proliferation and migration. Sirt7 promotes in the mouse by inhibiting autocatalytic activation of Sirt1. SAMHD1 acetylation enhances its deoxynucleotide triphosphohydrolase activity and promotes canc CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis. NOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to d NOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to d Acetylation Regulates Thioredoxin Reductase Oligomerization and Activity. Acetylation of TBX5 by KAT2B and KAT2A regulates heart and limb development. Acetyl-CoA Carboxylase 1-Dependent Protein Acetylation Controls Breast Cancer Metastasis and Re Acetylation of 53BP1 dictates the DNA double strand break repair pathway. Sirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein. HDAC1 regulates the stability of glutamate carboxypeptidase II protein by modulating acetylation st GATA3 acetylation at K119 by CBP inhibits cell migration and invasion in lung adenocarcinoma. suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, tra Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation a Acetylation within the N- and C-Terminal Domains of Src Regulates Distinct Roles of STAT3-Mediate CoA synthase regulates mitotic fidelity via CBP-mediated acetylation. Reversible Notch1 acetylation tunes proliferative signalling in cardiomyocytes. Sirtuin 3-induced macrophage autophagy in regulating NLRP3 inflammasome activation. Novel function of HATs and HDACs in homologous recombination through acetylation of human RA Post-translational modifications in DNA topoisomerase 2α highlight the role of a eukaryote-specific Aromatase Acetylation Patterns and Altered Activity in Response to Sirtuin Inhibition. 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