Metabolism is regulated by protein acetylation

Abstract

Lysine acetylation, first identified in histones, was initially thought to be a posttranslational modification occuring only in eukaryotic cells that controlled gene transcription either via remodeling chromatin or altering the transcriptional machinery. Recent studies, however, have shown that acetylation is a well-conserved metabolic regulatory mechanism that plays critical roles in regulating and coordinating cell metabolism. Acetylation regulates metabolism through controlling gene transcription, altering the metabolic enzymes activity and possibly other functional aspects, of metabolic enzymes. In this review, we provide an overview of the roles and significance of acetylation in metabolic regulation.

Keywords

acetylation / metabolism / regulation

References

[1] Allfrey V G, Faulkner R, Mirsky A E (1964). Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci U S A, 51(5): 786–794

[2] Banks A S, Kon N, Knight C, Matsumoto M, Gutiérrez-Juárez R, Rossetti L, Gu W, Accili D (2008). SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab, 8(4): 333–341

[3] Briere J J, Favier J, Bénit P, El Ghouzzi V, Lorenzato A, Rabier D, Di Renzo M F, Gimenez-Roqueplo A P, Rustin P (2005). Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions. Hum Mol Genet, 14(21): 3263–3269

[4] Chang K T, Min K T (2002) Regulation of lifespan by histone deacetylase. Ageing Res Rev, 1(3): 313–326

[5] Choudhary C, Kumar C, Gnad F, Nielsen M L, Rehman M, Walther T C, Olsen J V, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science, 325(5942): 834–840

[6] Dryden S C, Nahhas F A, Nowak J E, Goustin A S, Tainsky M A (2003) Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol, 23(9): 3173–3185

[7] Erion D M, Yonemitsu S, Nie Y, Nagai Y, Gillum M P, Hsiao J J, Iwasaki T, Stark R, Weismann D, Yu X X, Murray S F, Bhanot S, Monia B P, Horvath T L, Gao Q, Samuel V T, Shulman G I (2009). SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Proc Natl Acad Sci U S A, 106(27): 11288–11293

[8] Feige J N, Lagouge M, Canto C, Strehle A, Houten S M, Milne J C, Lambert P D, Mataki C, Elliott P J, Auwerx J (2008). Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab, 8(5): 347–358

[9] Frye R A (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun, 273(2): 793–798

[10] Gerhart-Hines Z, Rodgers J T, Bare O, Lerin C, Kim S H, Mostoslavsky R, Alt F W, Wu Z, Puigserver P (2007). Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J, 26(7): 1913–1923

[11] Grunstein M (1997) Histone acetylation in chromatin structure and transcription. Nature, 389(6649): 349–352

[12] Hallows W C, Lee S, Denu J M (2006). Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A, 103(27): 10230–10235

[13] Hirschey M D, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard D B, Grueter C A, Harris C, Biddinger S, Ilkayeva O R, Stevens R D, Li Y, Saha A K, Ruderman N B, Bain J R, Newgard C B, Farese R V Jr, Alt F W, Kahn C R, Verdin E (2010). SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature, 464(7285): 121–125

[14] Hou X, Xu S, Maitland-Toolan K A, Sato K, Jiang B, Ido Y, Lan F, Walsh K, Wierzbicki M, Verbeuren T J, Cohen R A, Zang M (2008). SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem, 283(29): 20015–20026

[15] Kim S C, Sprung R, Chen Y, Xu Y, Ball H, Pei J, Cheng T, Kho Y, Xiao H, Xiao L, Grishin N V, White M, Yang X J, Zhao Y M (2006). Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell, 23(4): 607–618

[16] Li X, Zhang S, Blander G, Tse J G, Krieger M, Guarente L (2007). SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell, 28(1): 91–106

[17] Lin Y Y, Lu J Y, Zhang J, Walter W, Dang W, Wan J, Tao S C, Qian J, Zhao Y, Boeke J D, Berger S L, Zhu H (2009). Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis. Cell, 136(6): 1073–1084

[18] Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, Milne J, Meyers D J, Cole P, Yates J 3rd, Olefsky J, Guarente L, Montminy M (2008). A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature, 456(7219): 269–273

[19] Nakagawa T, Lomb D J, Haigis M C, Guarente L (2009). SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell, 137(3): 560–570

[20] Nie Y, Erion D M, Yuan Z, Dietrich M, Shulman G I, Horvath T L, Gao Q (2009). STAT3 inhibition of gluconeogenesis is downregulated by SirT1. Nat Cell Biol, 11(4): 492–500

[21] Phillips D M (1963). The presence of acetyl groups of histones. Biochem J, 87: 258–263

[22] Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney M W, Guarente L (2004). Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature, 429(6993): 771–776

[23] Purushotham A, Schug T T, Xu Q, Surapureddi S, Guo X, Li X (2009). Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab, 9(4): 327–338

[24] Ratcliffe P J (2007). Fumarate hydratase deficiency and cancer: activation of hypoxia signaling? Cancer Cell, 11(4): 303–305

[25] Rine J, Herskowitz I (1987). Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics, 116(1): 9–22

[26] Rodgers J T, Lerin C, Haas W, Gygi S P, Spiegelman B M, Puigserver P (2005). Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature, 434(7029): 113–118

[27] Rodgers J T, Puigserver P (2007). Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A, 104(31): 12861–12866

[28] Schwer B, Bunkenborg J, Verdin R O, Andersen J S, Verdin E (2006). Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci U S A, 103(27): 10224–10229

[29] Someya S, Yu W, Hallows W C, Xu J, Vann J M, Leeuwenburgh C, Tanokura M, Denu J M, Prolla T A (2010). Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell, 143(5): 802–812

[30] Starai V J, Celic I, Cole R N, Boeke J D, Escalante-Semerena J C (2002) Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine. Science, 298(5602): 2390–2392

[31] Ventura M, Mateo F, Serratosa J, Salaet I, Carujo S, Bachs O, Pujol M J (2010). Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase is regulated by acetylation. Int J Biochem Cell Biol, 42(10): 1672–1680

[32] Wang Q, Zhang Y, Yang C, Xiong H, Lin Y, Yao J, Li H, Xie L, Zhao W, Yao Y, Ning Z B, Zeng R, Xiong Y, Guang K L, Zhao S, Zhao G F(2010). Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. Science, 327(5968): 1004–1007

[33] Yu W, Lin Y, Yao J, Huang W, Lei Q, Xiong Y, Zhao S, Guan K L (2009). Lysine 88 acetylation negatively regulates ornithine carbamoyltransferase activity in response to nutrient signals. J Biol Chem, 284(20): 13669–13675

[34] Zhang J, Sprung R, Pei J, Tan X, Kim S, Zhu H, Liu C F, Grishin N V, Zhao Y (2009). Lysine acetylation is a highly abundant and evolutionarily conserved modification in Escherichia coli. Mol Cell Proteomics, 8(2): 215–225

[35] Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H, Li Y, Shi J, An W, Hancock S M, He F, Qin L, Chin J, Yang P, Chen X, Lei Q, Xiong Y, Guan K L (2010). Regulation of cellular metabolism by protein lysine acetylation. Science, 327(5968): 1000–1004

[36] Zhao Y, Lu J, Sun H, Chen X, Huang W, Tao D, Huang B (2005). Histone acetylation regulates both transcription initiation and elongation of hsp22 gene in Drosophila. Biochem Biophys Res Commun, 326(4): 811–816

[37] Zheng L, Roeder R G, Luo Y (2003). S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell, 114(2): 255–266

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