Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation
2015; Elsevier BV; Volume: 14; Issue: 9 Linguagem: Inglês
10.1074/mcp.r114.046664
ISSN1535-9484
AutoresMatthew D. Hirschey, Yingming Zhao,
Tópico(s)Adipose Tissue and Metabolism
ResumoProtein acetylation is a well-studied regulatory mechanism for several cellular processes, ranging from gene expression to metabolism. Recent discoveries of new post-translational modifications, including malonylation, succinylation, and glutarylation, have expanded our understanding of the types of modifications found on proteins. These three acidic lysine modifications are structurally similar but have the potential to regulate different proteins in different pathways. The deacylase sirtuin 5 (SIRT5) catalyzes the removal of these modifications from a wide range of proteins in different subcellular compartments. Here, we review these new modifications, their regulation by SIRT5, and their emerging role in cellular regulation and diseases. Protein acetylation is a well-studied regulatory mechanism for several cellular processes, ranging from gene expression to metabolism. Recent discoveries of new post-translational modifications, including malonylation, succinylation, and glutarylation, have expanded our understanding of the types of modifications found on proteins. These three acidic lysine modifications are structurally similar but have the potential to regulate different proteins in different pathways. The deacylase sirtuin 5 (SIRT5) catalyzes the removal of these modifications from a wide range of proteins in different subcellular compartments. Here, we review these new modifications, their regulation by SIRT5, and their emerging role in cellular regulation and diseases. Lysine acetylation (Kac)1 is the addition of acetyl group to the ε-amine of a lysine side chain. This chemical modification is a reversible, dynamic, and evolutionarily conserved protein post-translational modification (PTM) (Fig. 1). 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Dai L. Tan M. Cheng Z. Wu Y. Boeke J.D. Zhao Y. Lysine succinylation and lysine malonylation in histones.Mol. Cell. Proteomics. 2012; 11: 100-107Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar, 28.Zhang Z. Tan M. Xie Z. Dai L. Chen Y. Zhao Y. Identification of lysine succinylation as a new post-translational modification.Nat. Chem. Biol. 2011; 7: 58-63Crossref PubMed Scopus (569) Google Scholar), and lysine glutarylation (Kglu) (29.Tan M. Peng C. Anderson K.A. Chhoy P. Xie Z. Dai L. Park J. Chen Y. Huang H. Zhang Y. Ro J. Wagner G.R. Green M.F. Madsen A.S. Schmiesing J. Peterson B.S. Xu G. Ilkayeva O.R. Muehlbauer M.J. Braulke T. Mühlhausen C. Backos D.S. Olsen C.A. McGuire P.J. Pletcher S.D. Lombard D.B. Hirschey M.D. Zhao Y. Lysine glutarylation is a protein post-translational modification regulated by SIRT5.Cell Metab. 2014; 19: 605-617Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar), which are collectively referred to as lysine acylation (Fig. 2). Similar to lysine acetylation, emerging evidence suggests that these new lysine acylations are important in regulating cellular metabolism in physiological and pathophysiological states. In this review, we describe these new modifications and their regulation and highlight their emerging role in cellular regulation. Recently identified lysine acyl modifications, Kmal (26.Peng C. Lu Z. Xie Z. Cheng Z. Chen Y. Tan M. Luo H. Zhang Y. He W. Yang K. Zwaans B.M. Tishkoff D. Ho L. Lombard D. He T.C. Dai J. Verdin E. Ye Y. Zhao Y. The first identification of lysine malonylation substrates and its regulatory enzyme.Mol. Cell. Proteomics. 2011; 10Abstract Full Text Full Text PDF Scopus (511) Google Scholar,27.Xie Z. Dai J. Dai L. Tan M. Cheng Z. 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Lysine glutarylation is a protein post-translational modification regulated by SIRT5.Cell Metab. 2014; 19: 605-617Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar) (Fig. 2), are evolutionarily conserved and dynamic under diverse cellular conditions, such as stressors, metabolic substrates and availability, and genetic mutations (29.Tan M. Peng C. Anderson K.A. Chhoy P. Xie Z. Dai L. Park J. Chen Y. Huang H. Zhang Y. Ro J. Wagner G.R. Green M.F. Madsen A.S. Schmiesing J. Peterson B.S. Xu G. Ilkayeva O.R. Muehlbauer M.J. Braulke T. Mühlhausen C. Backos D.S. Olsen C.A. McGuire P.J. Pletcher S.D. Lombard D.B. Hirschey M.D. Zhao Y. Lysine glutarylation is a protein post-translational modification regulated by SIRT5.Cell Metab. 2014; 19: 605-617Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar, 30.Pougovkina O. te Brinke H. Wanders R.J. Houten S.M. de Boer V.C. Aberrant protein acylation is a common observation in inborn errors of acyl-CoA metabolism.J. 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These CoAs can possibly be synthesized by their corresponding short-chain acyl salts, malonate, succinate, and glutarate, catalyzed by acyl-CoA synthetases, such as succinyl-CoA synthetase and malonyl-CoA synthetase (33.Fraser M.E. Hayakawa K. Hume M.S. Ryan D.G. Brownie E.R. Interactions of GTP with the ATP-grasp domain of GTP-specific succinyl-CoA synthetase.J. Biol. Chem. 2006; 281: 11058-11065Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 34.Witkowski A. Thweatt J. Smith S. Mammalian ACSF3 protein is a malonyl-CoA synthetase that supplies the chain extender units for mitochondrial fatty acid synthesis.J. Biol. Chem. 2011; 286: 33729-33736Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Additionally, these CoAs can be generated and consumed in the TCA cycle, as well as by metabolism of amino acids and lipids. These CoAs are highly regulated in cells and tissues. For example, dysregulation of malonyl-CoA is associated with diseases, such as ischemic heart disease and diabetes (35.Ruderman N. Prentki M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome.Nat. Rev. Drug Discov. 2004; 3: 340-351Crossref PubMed Scopus (375) Google Scholar, 36.Wolfgang M.J. Lane M.D. Hypothalamic malonyl-CoA and CPT1c in the treatment of obesity.FEBS J. 2011; 278: 552-558Crossref PubMed Scopus (51) Google Scholar). Additionally, these short-chain CoAs are thermodynamically favorable for their corresponding lysine acylation reactions (37.Wagner G.R. Hirschey M.D. Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases.Mol. Cell. 2014; 54: 5-16Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). Further, these CoAs are structurally similar to acetyl-CoA, leading to apparent enzymatically catalyzed acylation by promiscuous acetyltransferases. For example, the binding pocket of Hat1 has a large enough CoA binding pocket to accommodate CoAs larger than acetyl CoA (38.Dutnall R.N. Tafrov S.T. Sternglanz R. Ramakrishnan V. Structure of the yeast histone acetyltransferase Hat1: Insights into substrate specificity and implications for the Gcn5-related N-acetyltransferase superfamily.Cold Spring Harb. Symp. Quant. Biol. 1998; 63: 501-507Crossref PubMed Scopus (18) Google Scholar), such as malonyl-CoA, succinyl-CoA, or glutaryl-CoA. Acidic modifications are chemically different from lysine acetylation in two distinct ways. First, they add a bulkier acyl group to lysines compared with acetylation: three, four, or five carbons for malonylation, succinylation, or glutarylation, respectively, compared with two carbons for acetylation. Second, acidic modifications change the charge on lysine from +1 to −1 under physiological conditions (28.Zhang Z. Tan M. Xie Z. Dai L. Chen Y. Zhao Y. Identification of lysine succinylation as a new post-translational modification.Nat. Chem. Biol. 2011; 7: 58-63Crossref PubMed Scopus (569) Google Scholar). Interestingly, protein phosphorylation also generates a −1 charge on proteins. In contrast, lysine acetylation changes the charge on lysine from +1 to 0. Because of this difference, it is conceivable that acidic modifications could disrupt any ionic interactions between the positively charged, unmodified lysine side chains with a negative charged chemical moiety in other molecules, such as nucleotides, proteins, or small molecules. Alternatively, changes in lysine charge could impart structural alterations on proteins, as acidic modifications would be predicted to have a more profound impact on protein structure and function compared with lysine acetylation, if located in the same lysine site. Future studies will address these possibilities and determine how acidic acyl modifications influence protein function. Two groups of enzymes with opposing activities, lysine acetyltransferases and deacetylases (Box1), are known to regulate the status of lysine acetylation (Fig. 1) (39.Yang X.J. Seto E. HATs and HDACs: From structure, function and regulation to novel strategies for therapy and prevention.Oncogene. 2007; 26: 5310-5318Crossref PubMed Scopus (768) Google Scholar). Eighteen known class I, class II, and class IV histone deacetylases (HDAC1–11) and seven class III HDACs (the sirtuin family SIRT1–7) make up the entire HDAC family (Box 1). The HDACs have been a subject of intense study since their discovery in 1996 (40.Taunton J. Hassig C.A. Schreiber S.L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p.Science. 1996; 272: 408-411Crossref PubMed Scopus (1530) Google Scholar). Indeed, they have important roles in several areas of biology and disease and are increasingly used as targets for drug design. For example, deacetylase inhibitors, such as vorinnostat (trade name Zolinza) and romidepsin (trade name Istodax), have been approved by the U.S. Food and Drug Administration for clinical use in cancer therapy (41.Marks P.A. Breslow R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug.Nat. Biotechnol. 2007; 25: 84-90Crossref PubMed Scopus (976) Google Scholar, 42.Guan P. Fang H. Clinical development of histone deacetylase inhibitor romidepsin.Drug Discov. Ther. 2010; 4: 388-391PubMed Google Scholar). The sirtuin family of HDACs has seven highly conserved NAD+-dependent deacetylases, which were discovered in 1999/2000 (43.Frye R.A. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins.Biochem. Biophys. Res. Commun. 2000; 273: 793-798Crossref PubMed Scopus (1153) Google Scholar, 44.Frye R.A. 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In contrast, neither SIRT4 nor SIRT5 have been shown to regulate global mitochondrial protein acetylation levels (47.Lombard D.B. Alt F.W. Cheng H.L. Bunkenborg J. Streeper R.S. Mostoslavsky R. Kim J. Yancopoulos G. Valenzuela D. Murphy A. Yang Y. Chen Y. Hirschey M.D. Bronson R.T. Haigis M. Guarente L.P. Farese Jr., R.V. Weissman S. Verdin E. Schwer B. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation.Mol. Cell. Biol. 2007; 27: 8807-8814Crossref PubMed Scopus (965) Google Scholar). Supporting this idea, SIRT4 and SIRT5 have weak or nondetectable deacetylase activity in vitro. Low activities of these mitochondrial sirtuins against acetyl-lysine, and the absence of known substrates suggested the possibility they could be removing lysine modifications other than acetylation from proteins. The immediate question after the discovery of acidic acyl modifications was whether they were regulated by HDACs or HDAC-like enzymes. Given the same amide bonds between lysine acetylation and the acidic acyl modifications (Fig. 2), all 18 HDACs were tested for deacylation activities against malonylation, succinylation, and glutarylation. SIRT5 was shown to have potent demalonylase and desuccinylase activities; this finding was validated using biochemical measurements, as well as quantitative proteomics in cells and tissues, with or without an expression of SIRT5, both in vitro and in vivo (26.Peng C. Lu Z. Xie Z. Cheng Z. Chen Y. Tan M. Luo H. Zhang Y. He W. Yang K. Zwaans B.M. Tishkoff D. Ho L. Lombard D. He T.C. Dai J. Verdin E. Ye Y. Zhao Y. The first identification of lysine malonylation substrates and its regulatory enzyme.Mol. Cell. Proteomics. 2011; 10Abstract Full Text Full Text PDF Scopus (511) Google Scholar, 48.Park J. Chen Y. Tishkoff D.X. Peng C. Tan M. Dai L. Xie Z. Zhang Y. Zwaans B.M. Skinner M.E. Lombard D.B. Zhao Y. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways.Mol. Cell. 2013; 50: 919-930Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar). Importantly, these findings were independently discovered and verified using different, but complementary, methods, including enzymology and structural biology (49.Du J. Zhou Y. Su X. Yu J.J. Khan S. Jiang H. Kim J. Woo J. Kim J.H. Choi B.H. He B. Chen W. Zhang S. Cerione R.A. Auwerx J. Hao Q. Lin H. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase.Science. 2011; 334: 806-809Crossref PubMed Scopus (954) Google Scholar). In another recent study using quantitative proteomics, SIRT5 knockout mouse embryonic fibroblasts were shown to have an increase in lysine succinylation but not acetylation. Together, these studies demonstrate that SIRT5 is the major enzyme for lysine desuccinylation in the cells and tissues (48.Park J. Chen Y. Tishkoff D.X. Peng C. Tan M. Dai L. Xie Z. Zhang Y. Zwaans B.M. Skinner M.E. Lombard D.B. Zhao Y. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways.Mol. Cell. 2013; 50: 919-930Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar). Importantly, this result, combined with emerging evidence from other studies, also suggests SIRT5 is unlikely a deacetylase (Box1) in vivo. For example, in vitro deacetylation activities of SIRT5 is low or undetectable when measured using multiple substrates such as small molecules containing a florescent acetylated lysine residue, peptide substrate, and whole cell lysate (26.Peng C. Lu Z. Xie Z. Cheng Z. Chen Y. Tan M. Luo H. Zhang Y. He W. Yang K. Zwaans B.M. Tishkoff D. Ho L. Lombard D. He T.C. Dai J. Verdin E. Ye Y. Zhao Y. The first identification of lysine malonylation substrates and its regulatory enzyme.Mol. Cell. Proteomics. 2011; 10Abstract Full Text Full Text PDF Scopus (511) Google Scholar, 48.Park J. Chen Y. Tishkoff D.X. Peng C. Tan M. Dai L. Xie Z. Zhang Y. Zwaans B.M. Skinner M.E. Lombard D.B. Zhao Y. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways.Mol. Cell. 2013; 50: 919-930Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar). The current model is for SIRT5 to be a specific mammalian HDAC with potent activity to remove acidic lysine acyl groups. While mammalian SIRT5 seems to have activities restricted to acidic lysine acylation, its bacterial counterpart, CobB, the only deacetylase identified so far in prokaryotes, has both deacetylase and desuccinylase activities (50.Colak G. Xie Z. Zhu A.Y. Dai L. Lu Z. Zhang Y. Wan X. Chen Y. Cha Y.H. Lin H. Zhao Y. Tan M. Identification of lysine succinylation substrates and the succinylation regulatory enzyme CobB in Escherichia coli.Mol. Cell. Proteomics. 2013; 12: 3509-3520Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). Interestingly, CobB mutants can be generated in such a way that the two activities can be differentiated (50.Colak G. Xie Z. Zhu A.Y. Dai L. Lu Z. Zhang Y. Wan X. Chen Y. Cha Y.H. Lin H. Zhao Y. Tan M. Identification of lysine succinylation substrates and the succinylation regulatory enzyme CobB in Escherichia coli.Mol. Cell. Proteomics. 2013; 12: 3509-3520Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar), and more work will be required to understand the regulation of protein succinylation in lower organisms. In addition to lysine malonylation and lysine succinylation, a recent study demonstrated lysine glutarylation as a new lysine acylation and showed that SIRT5 is its deglutarylase (29.Tan M. Peng C. Anderson K.A. Chhoy P. Xie Z. Dai L. Park J. Chen Y. Huang H. Zhang Y. Ro J. Wagner G.R. Green M.F. Madsen A.S. Schmiesing J. Peterson B.S. Xu G. Ilkayeva O.R. Muehlbauer M.J. Braulke T. Mühlhausen C. Backos D.S. Olsen C.A. McGuire P.J. Pletcher S.D. Lombard D.B. Hirschey M.D. Zhao Y. Lysine glutarylation is a protein post-translational modification regulated by SIRT5.Cell Metab. 2014; 19: 605-617Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar), consistent with the idea that SIRT5 catalyzes the removal of acidic lysine modifications. Enzymatic studies and structural modeling show that SIRT5 has comparable activities among the three acyl modifications and prefers short-chain carboxylic groups, such as malonyl, succinyl, and glutaryl groups, but not acetyl (shorter) or adipoyl carboxylic groups (with a longer acidic acyl chain, e.g. six carbons or longer) (29.Tan M. Peng C. Anderson K.A. Chhoy P. Xie Z. Dai L. Park J. Chen Y. Huang H. Zhang Y. Ro J. Wagner G.R. Green M.F. Madsen A.S. Schmiesing J. Peterson B.S. Xu G. Ilkayeva O.R. Muehlbauer M.J. Braulke T. Mühlhausen C. Backos D.S. Olsen C.A. McGuire P.J. Pletcher S.D. Lombard D.B. Hirschey M.D. Zhao Y. Lysine glutarylation is a protein post-translational modification regulated by SIRT5.Cell Metab. 2014; 19: 605-617Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar). Thus, while SI
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