Skip to main content
SpringerLink
Log in

Post-translational Modification

  • Chapter
Congenital Heart Diseases: The Broken Heart

  • 2298 Accesses

Abstract

Posttranslational modifications, including chemical and covalent conjugation of small proteins, play dynamic regulatory roles underlying the functional modulation of proteins. Posttranslational modifications mediate virtually all cellular processes including cell proliferation, differentiation, apoptosis, and epigenetics in both physiological and pathophysiological conditions. In this chapter, we will summarize the major progresses in this field and expect to help to understand the importance of acetylation, methylation, ubiquitination, and SUMO conjugation in cardiac function and diseases. Reviews on phosphorylation posttranslational modifications were excluded because of space.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Stark GR, Wang Y, Lu T (2011) Lysine methylation of promoter-bound transcription factors and relevance to cancer. Cell Res 21:375–380

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Mostaqul Huq MD, Gupta P, Tsai NP et al (2006) Suppression of receptor interacting protein 140 repressive activity by protein arginine methylation. EMBO J 25:5094–5104

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Xu W, Chen H, Du K et al (2001) A transcriptional switch mediated by cofactor methylation. Science 294:2507–2511

    Article  CAS  PubMed  Google Scholar 

  4. Chevillard-Briet M, Trouche D, Vandel L (2002) Control of CBP co-activating activity by arginine methylation. EMBO J 21:5457–5466

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Paik WK, Cho YB, Frost B et al (1989) Cytochrome c methylation. Biochem Cell Biol 67:602–611

    Article  CAS  PubMed  Google Scholar 

  6. Sitaramayya A, Wright LS, Siegel FL (1980) Enzymatic methylation of calmodulin in rat brain cytosol. J Biol Chem 255:8894–8900

    CAS  PubMed  Google Scholar 

  7. Bauer UM, Daujat S, Nielsen SJ et al (2002) Methylation at arginine 17 of histone H3 is linked to gene activation. EMBO Rep 3:39–44

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Murata K, Kouzarides T, Bannister AJ et al (2010) Histone H3 lysine 4 methylation is associated with the transcriptional reprogramming efficiency of somatic nuclei by oocytes. Epigenetics Chromatin 3:4

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Nguyen CT, Weisenberger DJ, Velicescu M et al (2002) Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine. Cancer Res 62:6456–6461

    CAS  PubMed  Google Scholar 

  10. Klose RJ, Zhang Y (2007) Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol 8:307–318

    Article  CAS  PubMed  Google Scholar 

  11. Kaneda R, Takada S, Yamashita Y et al (2009) Genome-wide histone methylation profile for heart failure. Genes Cells 14:69–77

    Article  CAS  PubMed  Google Scholar 

  12. Pasini D, Bracken AP, Jensen MR et al (2004) Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 23:4061–4071

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Cao R, Zhang Y (2004) SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell 15:57–67

    Article  CAS  PubMed  Google Scholar 

  14. Shi B, Liang J, Yang X et al (2007) Shang, Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol 27:5105–5119

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Chen L, Ma Y, Kim EY et al (2012) Conditional ablation of ezh2 in murine hearts reveals its essential roles in endocardial cushion formation, cardiomyocyte proliferation and survival. PLoS One 7, e31005

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. He A, Ma Q, Cao J et al (2012) Polycomb repressive complex 2 regulates normal development of the mouse heart. Circ Res 110:406–415

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Moskowitz IP, Wang J, Peterson MA et al (2011) Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. Proc Natl Acad Sci U S A 108:4006–4011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. He A, Shen X, Ma Q et al (2012) PRC2 directly methylates GATA4 and represses its transcriptional activity. Genes Dev 26:37–42

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Sakata Y, Koibuchi N, Xiang F et al (2006) The spectrum of cardiovascular anomalies in CHF1/Hey2 deficient mice reveals roles in endocardial cushion, myocardial and vascular maturation. J Mol Cell Cardiol 40:267–273

    Article  CAS  PubMed  Google Scholar 

  20. Delgado-Olguin P, Huang Y, Li X et al (2012) Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat Genet 44:343–347

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Jones B, Su H, Bhat A et al (2008) The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. PLoS Genet 4, e1000190

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Nguyen AT, Xiao B, Neppl RL et al (2011) DOT1L regulates dystrophin expression and is critical for cardiac function. Genes Dev 25:263–274

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Lohan J, Culligan K, Ohlendieck K (2005) Deficiency in cardiac dystrophin affects the abundance of the alpha/beta-dystroglycan complex. J Biomed Biotechnol 2005:28–36

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Shen X, Kim W, Fujiwara Y et al (2009) Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell 139:1303–1314

    Article  PubMed Central  PubMed  Google Scholar 

  25. Takahashi M, Kojima M, Nakajima K et al (2004) Cardiac abnormalities cause early lethality of jumonji mutant mice. Biochem Biophys Res Commun 324:1319–1323

    Article  CAS  PubMed  Google Scholar 

  26. Lee Y, Song AJ, Baker R et al (2000) Jumonji, a nuclear protein that is necessary for normal heart development. Circ Res 86:932–938

    Article  CAS  PubMed  Google Scholar 

  27. Mysliwiec MR, Bresnick EH, Lee Y (2011) Endothelial Jarid2/Jumonji is required for normal cardiac development and proper Notch1 expression. J Biol Chem 286:17193–17204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Niessen K, Karsan A (2008) Notch signaling in cardiac development. Circ Res 102:1169–1181

    Article  CAS  PubMed  Google Scholar 

  29. Ulucan O, Keskin O, Erman B et al (2011) A comparative molecular dynamics study of methylation state specificity of JMJD2A. PLoS One 6, e24664

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Klose RJ, Yamane K, Bae Y et al (2006) The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442:312–316

    Article  CAS  PubMed  Google Scholar 

  31. Zhang QJ, Chen HZ, Wang L et al (2011) The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J Clin Invest 121:2447–2456

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Friedrich FW, Wilding BR, Reischmann S et al (2012) Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. Hum Mol Genet 21:3237–3254

    Article  CAS  PubMed  Google Scholar 

  33. Sheikh F, Raskin A, Chu PH et al (2008) An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice. J Clin Invest 118:3870–3880

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Verrier L, Escaffit F, Chailleux C et al (2011) A new isoform of the histone demethylase JMJD2A/KDM4A is required for skeletal muscle differentiation. PLoS Genet 7, e1001390

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Bose J, Gruber AD, Helming L et al (2004) The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal. J Biol 3:15

    Article  PubMed Central  PubMed  Google Scholar 

  36. Chang B, Chen Y, Zhao Y, Bruick RK (2007) JMJD6 is a histone arginine demethylase. Science 318:444–447

    Article  CAS  PubMed  Google Scholar 

  37. Pang M, Zhuang S (2010) Histone deacetylase: a potential therapeutic target for fibrotic disorders. J Pharmacol Exp Ther 335:266–272

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Dietz KC, Casaccia P (2010) HDAC inhibitors and neurodegeneration: at the edge between protection and damage. Pharmacol Res 62:11–17

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Kollar J, Frecer V (2015) Selective inhibitors of zinc-dependent histone deacetylases. Therapeutic Targets Relevant to Cancer. Curr Pharm Des 21:1472–1502

    Article  CAS  PubMed  Google Scholar 

  40. Lakshmaiah KC, Jacob LA, Aparna S et al (2014) Epigenetic therapy of cancer with histone deacetylase inhibitors. J Cancer Res Ther 10:469–478

    CAS  PubMed  Google Scholar 

  41. Roth SY, Denu JM, Allis CD (2001) Histone acetyltransferases. Annu Rev Biochem 70:81–120

    Article  CAS  PubMed  Google Scholar 

  42. Matus M, Lewin G, Stumpel F et al (2007) Cardiomyocyte-specific inactivation of transcription factor CREB in mice. FASEB J 21:1884–1892

    Article  CAS  PubMed  Google Scholar 

  43. Gusterson RJ, Jazrawi E, Adcock IM et al (2003) The transcriptional co-activators CREB-binding protein (CBP) and p300 play a critical role in cardiac hypertrophy that is dependent on their histone acetyltransferase activity. J Biol Chem 278:6838–6847

    Article  CAS  PubMed  Google Scholar 

  44. Yao TP, Oh SP, Fuchs M et al (1998) Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 93:361–372

    Article  CAS  PubMed  Google Scholar 

  45. Shikama N, Lutz W, Kretzschmar R et al (2003) Essential function of p300 acetyltransferase activity in heart, lung and small intestine formation. EMBO J 22:5175–5185

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Wei JQ, Shehadeh LA, Mitrani JM et al (2008) Bishopric, Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300. Circulation 118:934–946

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Yanazume T, Hasegawa K, Morimoto T et al (2003) Cardiac p300 is involved in myocyte growth with decompensated heart failure. Mol Cell Biol 23:3593–3606

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Miyamoto S, Kawamura T, Morimoto T et al (2006) Histone acetyltransferase activity of p300 is required for the promotion of left ventricular remodeling after myocardial infarction in adult mice in vivo. Circulation 113:679–690

    Article  CAS  PubMed  Google Scholar 

  49. Takaya T, Kawamura T, Morimoto T et al (2008) Identification of p300-targeted acetylated residues in GATA4 during hypertrophic responses in cardiac myocytes. J Biol Chem 283:9828–9835

    Article  CAS  PubMed  Google Scholar 

  50. Kawamura T, Ono K, Morimoto T et al (2005) Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes. J Biol Chem 280:19682–19688

    Article  CAS  PubMed  Google Scholar 

  51. Chandrasekaran S, Peterson RE, Mani SK et al (2009) Histone deacetylases facilitate sodium/calcium exchanger up-regulation in adult cardiomyocytes. FASEB J 23:3851–3864

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Wang D, Chang PS, Wang Z et al (2001) Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105:851–862

    Article  CAS  PubMed  Google Scholar 

  53. Huang J, Min Lu M, Cheng L et al (2009) Myocardin is required for cardiomyocyte survival and maintenance of heart function. Proc Natl Acad Sci U S A 106:18734–18739

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Ransom JF, King IN, Garg V et al (2008) A rare human sequence variant reveals myocardin autoinhibition. J Biol Chem 283:35845–35852

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Cao D, Wang C, Tang R et al (2012) Acetylation of myocardin is required for the activation of cardiac and smooth muscle genes. J Biol Chem 287:38495–38504

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Lin Q, Schwarz J, Bucana C et al (1997) Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276:1404–1407

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Xu J, Gong NL, Bodi I et al (2006) Myocyte enhancer factors 2A and 2C induce dilated cardiomyopathy in transgenic mice. J Biol Chem 281:9152–9162

    Article  CAS  PubMed  Google Scholar 

  58. Angelelli C, Magli A, Ferrari D et al (2008) Differentiation-dependent lysine 4 acetylation enhances MEF2C binding to DNA in skeletal muscle cells. Nucleic Acids Res 36:915–928

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Shindo T, Manabe I, Fukushima Y et al (2002) Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nat Med 8:856–863

    CAS  PubMed  Google Scholar 

  60. Miyamoto S, Suzuki T, Muto S et al (2003) Positive and negative regulation of the cardiovascular transcription factor KLF5 by p300 and the oncogenic regulator SET through interaction and acetylation on the DNA-binding domain. Mol Cell Biol 23:8528–8541

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Graef IA, Chen F, Crabtree GR (2001) NFAT signaling in vertebrate development. Curr Opin Genet Dev 11:505–512

    Article  CAS  PubMed  Google Scholar 

  62. Rao A, Luo C, Hogan PG (1997) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15:707–747

    Article  CAS  PubMed  Google Scholar 

  63. de la Pompa JL, Timmerman LA, Takimoto H et al (1998) Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature 392:182–186

    Article  PubMed  Google Scholar 

  64. Phoon CK, Ji RP, Aristizabal O et al (2004) Embryonic heart failure in NFATc1−/− mice: novel mechanistic insights from in utero ultrasound biomicroscopy. Circ Res 95:92–99

    Article  CAS  PubMed  Google Scholar 

  65. Kim JH, Kim K, Youn BU et al (2011) RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation. Biochem J 436:253–262

    Article  CAS  PubMed  Google Scholar 

  66. Meissner JD, Freund R, Krone D et al (2011) Extracellular signal-regulated kinase 1/2-mediated phosphorylation of p300 enhances myosin heavy chain I/beta gene expression via acetylation of nuclear factor of activated T cells c1. Nucleic Acids Res 39:5907–5925

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Waby JS, Chirakkal H, Yu C et al (2010) Sp1 acetylation is associated with loss of DNA binding at promoters associated with cell cycle arrest and cell death in a colon cell line. Mol Cancer 9:275

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  68. Greene WC, Chen LF (2004) Regulation of NF-kappaB action by reversible acetylation. Novartis Found Symp 259:208–217; discussion 218–225

    Article  CAS  PubMed  Google Scholar 

  69. Inoue Y, Itoh Y, Abe K et al (2007) Smad3 is acetylated by p300/CBP to regulate its transactivation activity. Oncogene 26:500–508

    Article  CAS  PubMed  Google Scholar 

  70. Grillon JM, Johnson KR, Kotlo K et al (2012) Non-histone lysine acetylated proteins in heart failure. Biochim Biophys Acta 1822:607–614

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Hirschey MD, Shimazu T, Goetzman E et al (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121–125

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Schwer B, Bunkenborg J, Verdin RO et al (2006) Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci U S A 103:10224–10229

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Bugger H, Schwarzer M, Chen D et al (2010) Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure. Cardiovasc Res 85:376–384

    Article  CAS  PubMed  Google Scholar 

  74. Karamanlidis G, Lee CF, Garcia-Menendez L et al (2013) Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab 18:239–250

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Marmorstein R (2001) Structure of histone deacetylases: insights into substrate recognition and catalysis. Structure 9:1127–1133

    Article  CAS  PubMed  Google Scholar 

  76. Lombardi PM, Cole KE, Dowling DP et al (2011) Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes. Curr Opin Struct Biol 21:735–743

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Imai S, Armstrong CM, Kaeberlein M et al (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403:795–800

    Article  CAS  PubMed  Google Scholar 

  78. Trivedi CM, Luo Y, Yin Z et al (2007) Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nat Med 13:324–331

    Article  CAS  PubMed  Google Scholar 

  79. Chang S, McKinsey TA, Zhang CL et al (2004) Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol 24:8467–8476

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Zhang CL, McKinsey TA, Chang S et al (2002) Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110:479–488

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Montgomery RL, Davis CA, Potthoff MJ et al (2007) Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev 21:1790–1802

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Singh N, Trivedi CM, Lu M et al (2011) Histone deacetylase 3 regulates smooth muscle differentiation in neural crest cells and development of the cardiac outflow tract. Circ Res 109:1240–1249

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Trivedi CM, Lu MM, Wang Q et al (2008) Transgenic overexpression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy. J Biol Chem 283:26484–26489

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Vega RB, Matsuda K, Oh J et al (2004) Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119:555–566

    Article  CAS  PubMed  Google Scholar 

  85. Demos-Davies KM, Ferguson BS, Cavasin MA et al (2014) HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling. Am J Physiol Heart Circ Physiol 307:H252–H258

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Chang S, Young BD, Li S et al (2006) Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Cell 126:321–334

    Article  CAS  PubMed  Google Scholar 

  87. Haberland M, Mokalled MH, Montgomery RL et al (2009) Epigenetic control of skull morphogenesis by histone deacetylase 8. Genes Dev 23:1625–1630

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Sahakian E, Powers JJ, Chen J et al (2015) Histone deacetylase 11: a novel epigenetic regulator of myeloid derived suppressor cell expansion and function. Mol Immunol 63:579–585

    Article  CAS  PubMed  Google Scholar 

  89. Bush EW, McKinsey TA (2010) Protein acetylation in the cardiorenal axis: the promise of histone deacetylase inhibitors. Circ Res 106:272–284

    Article  CAS  PubMed  Google Scholar 

  90. Backs J, Olson EN (2006) Control of cardiac growth by histone acetylation/deacetylation. Circ Res 98:15–24

    Article  CAS  PubMed  Google Scholar 

  91. Liu F, Levin MD, Petrenko NB et al (2008) Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin. J Mol Cell Cardiol 45:715–723

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Kong Y, Tannous P, Lu G et al (2006) Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation 113:2579–2588

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Cho YK, Eom GH, Kee HJ et al (2010) Sodium valproate, a histone deacetylase inhibitor, but not captopril, prevents right ventricular hypertrophy in rats. Circ J 74:760–770

    Article  CAS  PubMed  Google Scholar 

  94. McKinsey TA (2011) Targeting inflammation in heart failure with histone deacetylase inhibitors. Mol Med 17:434–441

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Goldstein G (1974) Isolation of bovine thymin: a polypeptide hormone of the thymus. Nature 247:11–14

    Article  CAS  PubMed  Google Scholar 

  97. Ciehanover A, Hod Y, Hershko A (1978) A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochem Biophys Res Commun 81:1100–1105

    Article  CAS  PubMed  Google Scholar 

  98. Wilkinson KD, Ventii KH, Friedrich KL et al (2005) The ubiquitin signal: assembly, recognition and termination. Symposium on ubiquitin and signaling. EMBO Rep 6:815–820

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10:550–563

    Article  CAS  PubMed  Google Scholar 

  100. Bova MP, Yaron O, Huang Q et al (1999) Mutation R120G in alphaB-crystallin, which is linked to a desmin-related myopathy, results in an irregular structure and defective chaperone-like function. Proc Natl Acad Sci U S A 96:6137–6142

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Vicart P, Caron A, Guicheney P et al (1998) A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 20:92–95

    Article  CAS  PubMed  Google Scholar 

  102. van Spaendonck-Zwarts K, van Hessem L, Jongbloed JD et al (2011) Desmin-related myopathy: a review and meta-analysis. Clin Genet 80(4):354–366

    Google Scholar 

  103. Wang X, Osinska H, Klevitsky R et al (2001) Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice. Circ Res 89:84–91

    Article  CAS  PubMed  Google Scholar 

  104. Chen Q, Liu JB, Horak KM et al (2005) Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake. Circ Res 97:1018–1026

    Article  CAS  PubMed  Google Scholar 

  105. Richard P, Charron P, Carrier L et al (2003) Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 107:2227–2232

    Article  PubMed  Google Scholar 

  106. Flashman E, Redwood C, Moolman-Smook J et al (2004) Cardiac myosin binding protein C: its role in physiology and disease. Circ Res 94:1279–1289

    Article  CAS  PubMed  Google Scholar 

  107. Sarikas A, Carrier L, Schenke C et al (2005) Impairment of the ubiquitin-proteasome system by truncated cardiac myosin binding protein C mutants. Cardiovasc Res 66:33–44

    Article  CAS  PubMed  Google Scholar 

  108. Yang Q, Sanbe A, Osinska H et al (1999) In vivo modeling of myosin binding protein C familial hypertrophic cardiomyopathy. Circ Res 85:841–847

    Article  CAS  PubMed  Google Scholar 

  109. Bulteau AL, Lundberg KC, Humphries KM et al (2001) Oxidative modification and inactivation of the proteasome during coronary occlusion/reperfusion. J Biol Chem 276:30057–30063

    Article  CAS  PubMed  Google Scholar 

  110. Powell SR, Herrmann J, Lerman A et al (2012) The ubiquitin-proteasome system and cardiovascular disease. Prog Mol Biol Transl Sci 109:295–346

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. Li J, Horak KM, Su H et al (2011) Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice. J Clin Invest 121:3689–3700

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  112. Tian Z, Zheng H, Li J et al (2012) Genetically induced moderate inhibition of the proteasome in cardiomyocytes exacerbates myocardial ischemia-reperfusion injury in mice. Circ Res 111:532–542

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. Powell SR, Davies KJ, Divald A (2007) Optimal determination of heart tissue 26S-proteasome activity requires maximal stimulating ATP concentrations. J Mol Cell Cardiol 42:265–269

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  114. Predmore JM, Wang P, Davis F et al (2010) Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies. Circulation 121:997–1004

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Tsukamoto O, Minamino T, Okada K et al (2006) Depression of proteasome activities during the progression of cardiac dysfunction in pressure-overloaded heart of mice. Biochem Biophys Res Commun 340:1125–1133

    Article  CAS  PubMed  Google Scholar 

  116. Depre C, Wang Q, Yan L et al (2006) Activation of the cardiac proteasome during pressure overload promotes ventricular hypertrophy. Circulation 114:1821–1828

    Article  CAS  PubMed  Google Scholar 

  117. Gurusamy N, Goswami S, Malik G et al (2008) Oxidative injury induces selective rather than global inhibition of proteasomal activity. J Mol Cell Cardiol 44:419–428

    Article  CAS  PubMed  Google Scholar 

  118. Gomes MD, Lecker SH, Jagoe RT et al (2001) Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A 98:14440–14445

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  119. Bodine SC, Latres E, Baumhueter S et al (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708

    Article  CAS  PubMed  Google Scholar 

  120. Wolska BM (2009) Calcineurin and cardiac function: is more or less better for the heart? Am J Physiol Heart Circ Physiol 297:H1576–H1577

    Article  CAS  PubMed  Google Scholar 

  121. Li HH, Kedar V, Zhang C et al (2004) Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. J Clin Invest 114:1058–1071

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Odashima M, Usui S, Takagi H et al (2007) Inhibition of endogenous Mst1 prevents apoptosis and cardiac dysfunction without affecting cardiac hypertrophy after myocardial infarction. Circ Res 100:1344–1352

    Article  CAS  PubMed  Google Scholar 

  123. Kedar V, McDonough H, Arya R et al (2004) Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I. Proc Natl Acad Sci U S A 101:18135–18140

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  124. Fielitz J, Kim MS, Shelton JM et al (2007) Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3. J Clin Invest 117:2486–2495

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Willis MS, Rojas M, Li L et al (2009) Muscle ring finger 1 mediates cardiac atrophy in vivo. Am J Physiol Heart Circ Physiol 296:H997–H1006

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  126. Hwee DT, Gomes AV, Bodine SC (2011) Cardiac proteasome activity in muscle ring finger-1 null mice at rest and following synthetic glucocorticoid treatment. Am J Physiol Endocrinol Metab 301:E967–E977

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  127. Willis MS, Schisler JC, Li L et al (2009) Cardiac muscle ring finger-1 increases susceptibility to heart failure in vivo. Circ Res 105:80–88

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  128. Foo RS, Chan LK, Kitsis RN (2007) etal. Ubiquitination and degradation of the anti-apoptotic protein ARC by MDM2. J Biol Chem 282:5529–5535

    Article  CAS  PubMed  Google Scholar 

  129. Toth A, Nickson P, Qin LL et al (2006) Differential regulation of cardiomyocyte survival and hypertrophy by MDM2, an E3 ubiquitin ligase. J Biol Chem 281:3679–3689

    Article  CAS  PubMed  Google Scholar 

  130. Haupt Y, Maya R, Kazaz A et al (1997) Mdm2 promotes the rapid degradation of p53. Nature 387:296–299

    Article  CAS  PubMed  Google Scholar 

  131. Kubbutat MH, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387:299–303

    Article  CAS  PubMed  Google Scholar 

  132. Shenoy SK, McDonald PH, Kohout TA et al (2001) Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294:1307–1313

    Article  CAS  PubMed  Google Scholar 

  133. Girnita L, Girnita A, Larsson O (2003) Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci U S A 100:8247–8252

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  134. Fu W, Ma Q, Chen L et al (2009) MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. J Biol Chem 284:13987–14000

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  135. Milkiewicz M, Roudier E, Doyle JL et al (2011) Identification of a mechanism underlying regulation of the anti-angiogenic forkhead transcription factor FoxO1 in cultured endothelial cells and ischemic muscle. Am J Pathol 178:935–944

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  136. Ballinger CA, Connell P, Wu Y et al (1999) Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 19:4535–4545

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  137. Schisler JC, Rubel CE, Zhang C et al (2013) CHIP protects against cardiac pressure overload through regulation of AMPK. J Clin Invest 123:3588–3599

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Naito AT, Okada S, Minamino T et al (2010) Promotion of CHIP-mediated p53 degradation protects the heart from ischemic injury. Circ Res 106:1692–1702

    Article  CAS  PubMed  Google Scholar 

  139. Li F, Xie P, Fan Y et al (2009) C terminus of Hsc70-interacting protein promotes smooth muscle cell proliferation and survival through ubiquitin-mediated degradation of FoxO1. J Biol Chem 284:20090–20098

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Esser C, Scheffner M, Hohfeld J (2005) The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. J Biol Chem 280:27443–27448

    Article  CAS  PubMed  Google Scholar 

  141. Nijman SM, Luna-Vargas MP, Velds A et al (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123:773–786

    Article  CAS  PubMed  Google Scholar 

  142. D’Arcy P, Linder S (2012) Proteasome deubiquitinases as novel targets for cancer therapy. Int J Biochem Cell Biol 44:1729–1738

    Article  PubMed  CAS  Google Scholar 

  143. Majumdar I, Paul J (2014) The deubiquitinase A20 in immunopathology of autoimmune diseases. Autoimmunity 47:307–319

    Article  CAS  PubMed  Google Scholar 

  144. D’Arcy P, Wang X, Linder S (2015) Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther 147C:32–54

    Article  CAS  Google Scholar 

  145. Reincke M, Sbiera S, Hayakawa A et al (2015) Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat Genet 47:31–38

    Article  CAS  PubMed  Google Scholar 

  146. Kostin S, Pool L, Elsasser A et al (2003) Myocytes die by multiple mechanisms in failing human hearts. Circ Res 92:715–724

    Article  CAS  PubMed  Google Scholar 

  147. Owerbach D, McKay EM, Yeh ET et al (2005) A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation. Biochem Biophys Res Commun 337:517–520

    Article  CAS  PubMed  Google Scholar 

  148. Ayaydin F, Dasso M (2004) Distinct in vivo dynamics of vertebrate SUMO paralogues. Mol Biol Cell 15:5208–5218

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  149. Saitoh H, Hinchey J (2000) Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem 275:6252–6258

    Article  CAS  PubMed  Google Scholar 

  150. Johnson ES (2004) Protein modification by sumo. Annu Rev Biochem 73:355–382

    Article  CAS  PubMed  Google Scholar 

  151. Kjenseth TA, Fykerud S (2012) Sirnes, et al. The gap junction channel protein connexin43 is covalently modified and regulated by SUMOylation. J Biol Chem 287:15851–15861

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  152. Martin S, Wilkinson KA, Nishimune A et al (2007) Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction. Nat Rev Neurosci 8:948–959

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  153. Harder Z, Zunino R, McBride H (2004) Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr Biol 14:340–345

    Article  CAS  PubMed  Google Scholar 

  154. Mabb AM, Wuerzberger-Davis SM, Miyamoto S (2006) PIASy mediates NEMO sumoylation and NF-kappaB activation in response to genotoxic stress. Nat Cell Biol 8:986–993

    Article  CAS  PubMed  Google Scholar 

  155. Rajan S, Plant LD, Rabin ML et al (2005) Sumoylation silences the plasma membrane leak K+ channel K2P1. Cell 121:37–47

    Article  CAS  PubMed  Google Scholar 

  156. Yang Y, Tse AK, Li P et al (2011) Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation. Oncogene 30:2207–2218

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Gregoire S, Yang XJ (2005) Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors. Mol Cell Biol 25:2273–2287

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  158. Zhao X, Sternsdorf T, Bolger TA et al (2005) Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol Cell Biol 25:8456–8464

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  159. Garcia-Gutierrez P, Juarez-Vicente F, Gallardo-Chamizo F et al (2011) The transcription factor Krox20 is an E3 ligase that sumoylates its Nab coregulators. EMBO Rep 12:1018–1023

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  160. Braschi E, Zunino R, McBride HM (2009) MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO Rep 10:748–754

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  161. Potts PR, Yu H (2007) The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins. Nat Struct Mol Biol 14:581–590

    Article  CAS  PubMed  Google Scholar 

  162. Kagey MH, Melhuish TA, Wotton D (2003) The polycomb protein Pc2 is a SUMO E3. Cell 113:127–137

    Article  CAS  PubMed  Google Scholar 

  163. Oh Y, Kim YM, Mouradian MM et al (2011) Human Polycomb protein 2 promotes alpha-synuclein aggregate formation through covalent SUMOylation. Brain Res 1381:78–89

    Article  CAS  PubMed  Google Scholar 

  164. Roscic A, Moller A, Calzado MA et al (2006) Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2. Mol Cell 24:77–89

    Article  CAS  PubMed  Google Scholar 

  165. Agrawal N, Banerjee R (2008) Human polycomb 2 protein is a SUMO E3 ligase and alleviates substrate-induced inhibition of cystathionine beta-synthase sumoylation. PLoS One 3, e4032

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  166. Deng Z, Wan M, Sui G (2007) PIASy-mediated sumoylation of Yin Yang 1 depends on their interaction but not the RING finger. Mol Cell Biol 27:3780–3792

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  167. Wang J, Feng XH, Schwartz RJ (2004) SUMO-1 modification activated GATA4-dependent cardiogenic gene activity. J Biol Chem 279:49091–49098

    Article  CAS  PubMed  Google Scholar 

  168. Kirsh O, Seeler JS, Pichler A et al (2002) The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J 21:2682–2691

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  169. Pichler A, Gast A, Seeler JS et al (2002) The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108:109–120

    Article  CAS  PubMed  Google Scholar 

  170. Dawlaty MM, Malureanu L, Jeganathan KB et al (2008) Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase IIalpha. Cell 133:103–115

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  171. Subramaniam S, Mealer RG, Sixt KM et al (2010) RHES, a physiologic regulator of sumoylation, enhances cross-sumoylation among the basic sumoylation enzymes E1 and UBC9. J Biol Chem 285:20428–20432

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  172. Pelisch F, Gerez J, Druker J et al (2010) The serine/arginine-rich protein SF2/ASF regulates protein sumoylation. Proc Natl Acad Sci U S A 107:16119–16124

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  173. Oh SM, Liu Z, Okada M et al (2010) Ebp1 sumoylation, regulated by TLS/FUS E3 ligase, is required for its anti-proliferative activity. Oncogene 29:1017–1030

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  174. Weger S, Hammer E, Heilbronn R (2005) Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS Lett 579:5007–5012

    Article  CAS  PubMed  Google Scholar 

  175. Pungaliya P, Kulkarni D, Park HJ et al (2007) TOPORS functions as a SUMO-1 E3 ligase for chromatin-modifying proteins. J Proteome Res 6:3918–3923

    Article  CAS  PubMed  Google Scholar 

  176. Morita Y, Kanei-Ishii C, Nomura T et al (2005) TRAF7 sequesters c-Myb to the cytoplasm by stimulating its sumoylation. Mol Biol Cell 16:5433–5444

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  177. Liang Q, Deng H, Li X et al (2011) Tripartite motif-containing protein 28 is a small ubiquitin-related modifier E3 ligase and negative regulator of IFN regulatory factor 7. J Immunol 187:4754–4763

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  178. Kotaja N, Karvonen U, Janne OA et al (2002) PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Mol Cell Biol 22:5222–5234

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  179. Wang J, Zhang H, Iyer D et al (2008) Regulation of cardiac specific nkx2.5 gene activity by small ubiquitin-like modifier. J Biol Chem 283:23235–23243

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  180. Wong KA, Kim R, Christofk H et al (2004) Protein inhibitor of activated STAT Y (PIASy) and a splice variant lacking exon 6 enhance sumoylation but are not essential for embryogenesis and adult life. Mol Cell Biol 24:5577–5586

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  181. Liu B, Mink S, Wong KA et al (2004) PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Nat Immunol 5:891–898

    Article  CAS  PubMed  Google Scholar 

  182. Yan W, Santti H, Janne OA et al (2003) Expression of the E3 SUMO-1 ligases PIASx and PIAS1 during spermatogenesis in the rat. Gene Expr Patterns 3:301–308

    Article  CAS  PubMed  Google Scholar 

  183. Roth W, Sustmann C, Kieslinger M et al (2004) PIASy-deficient mice display modest defects in IFN and Wnt signaling. J Immunol 173:6189–6199

    Article  CAS  PubMed  Google Scholar 

  184. Tahk S, Liu B, Chernishof V et al (2007) Control of specificity and magnitude of NF-kappa B and STAT1-mediated gene activation through PIASy and PIAS1 cooperation. Proc Natl Acad Sci U S A 104:11643–11648

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  185. Hay RT (2007) SUMO-specific proteases: a twist in the tail. Trends Cell Biol 17:370–376

    Article  CAS  PubMed  Google Scholar 

  186. Kolli N, Mikolajczyk J, Drag M et al (2010) Distribution and paralogue specificity of mammalian deSUMOylating enzymes. Biochem J 430:335–344

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  187. Mikolajczyk J, Drag M, Bekes M et al (2007) Small ubiquitin-related modifier (SUMO)-specific proteases: profiling the specificities and activities of human SENPs. J Biol Chem 282:26217–26224

    Article  CAS  PubMed  Google Scholar 

  188. Cheng J, Kang X, Zhang S et al (2007) SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell 131:584–595

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  189. Kang X, Qi Y, Zuo Y et al (2010) SUMO-specific protease 2 is essential for suppression of polycomb group protein-mediated gene silencing during embryonic development. Mol Cell 38:191–201

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  190. Yu L, Ji W, Zhang H et al (2010) SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis. J Exp Med 207:1183–1195

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  191. Rodriguez MS, Dargemont C, Hay RT (2001) SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J Biol Chem 276:12654–12659

    Article  CAS  PubMed  Google Scholar 

  192. Bernier-Villamor V, Sampson DA, Matunis MJ et al (2002) Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell 108:345–356

    Article  CAS  PubMed  Google Scholar 

  193. Comerford KM, Leonard MO, Karhausen J et al (2003) Small ubiquitin-related modifier-1 modification mediates resolution of CREB-dependent responses to hypoxia. Proc Natl Acad Sci U S A 100:986–991

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  194. Figueroa-Romero C, Iniguez-Lluhi JA, Stadler J et al (2009) SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J 23:3917–3927

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  195. Wang J, Li A, Wang Z et al (2007) Schwartz, Myocardin sumoylation transactivates cardiogenic genes in pluripotent 10T1/2 fibroblasts. Mol Cell Biol 27:622–632

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  196. Tatham MH, Jaffray E, Vaughan OA et al (2001) Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem 276:35368–35374

    Article  CAS  PubMed  Google Scholar 

  197. Woo CH, Shishido T, McClain C et al (2008) Extracellular signal-regulated kinase 5 SUMOylation antagonizes shear stress-induced antiinflammatory response and endothelial nitric oxide synthase expression in endothelial cells. Circ Res 102:538–545

    Article  CAS  PubMed  Google Scholar 

  198. Vu EH, Kraus RJ, Mertz JE (2007) Phosphorylation-dependent sumoylation of estrogen-related receptor alpha1. Biochemistry 46:9795–9804

    Article  CAS  PubMed  Google Scholar 

  199. Riising EM, Boggio R, Chiocca S et al (2008) The polycomb repressive complex 2 is a potential target of SUMO modifications. PLoS One 3, e2704

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  200. Zhang YQ, Sarge KD (2008) Sumoylation regulates lamin A function and is lost in lamin A mutants associated with familial cardiomyopathies. J Cell Biol 182:35–39

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  201. Gupta V, Bei M (2006) Modification of Msx1 by SUMO-1. Biochem Biophys Res Commun 345:74–77

    Article  CAS  PubMed  Google Scholar 

  202. Nayak A, Glockner-Pagel J, Vaeth M et al (2009) Sumoylation of the transcription factor NFATc1 leads to its subnuclear relocalization and interleukin-2 repression by histone deacetylase. J Biol Chem 284:10935–10946

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  203. Wang J, Zhang H, Iyer D et al (2008) Regulation of cardiac specific Nkx2.5 gene activity by sumo modification. J Biol Chem 283(34):23235–23243

    Google Scholar 

  204. Messner S, Schuermann D, Altmeyer M et al (2009) Sumoylation of poly(ADP-ribose) polymerase 1 inhibits its acetylation and restrains transcriptional coactivator function. FASEB J 23:3978–3989

    Article  CAS  PubMed  Google Scholar 

  205. Rytinki MM, Palvimo JJ (2009) SUMOylation attenuates the function of PGC-1alpha. J Biol Chem 284:26184–26193

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  206. Duan SZ, Ivashchenko CY, Russell MW et al (2005) Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice. Circ Res 97:372–379

    Article  CAS  PubMed  Google Scholar 

  207. Yamashita D, Yamaguchi T, Shimizu M et al (2004) The transactivating function of peroxisome proliferator-activated receptor gamma is negatively regulated by SUMO conjugation in the amino-terminal domain. Genes Cells 9:1017–1029

    Article  CAS  PubMed  Google Scholar 

  208. Ohshima T, Koga H, Shimotohno K (2004) Transcriptional activity of peroxisome proliferator-activated receptor-gamma is modulated by SUMO-1 modification. J Biol Chem 279:29551–29557

    Article  CAS  PubMed  Google Scholar 

  209. Pourcet B, Pineda-Torra I, Derudas B et al (2010) SUMOylation of human peroxisome proliferator-activated receptor alpha inhibits its trans-activity through the recruitment of the nuclear corepressor NCoR. J Biol Chem 285:5983–5992

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  210. Leuenberger N, Pradervand S, Wahli W (2009) Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice. J Clin Invest 119:3138–3148

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  211. Pan MR, Chang TM, Chang HC et al (2009) Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells. J Cell Sci 122:3358–3364

    Article  CAS  PubMed  Google Scholar 

  212. Shan SF, Wang LF, Zhai JW et al (2008) Modulation of transcriptional corepressor activity of prospero-related homeobox protein (Prox1) by SUMO modification. FEBS Lett 582:3723–3728

    Article  CAS  PubMed  Google Scholar 

  213. Choi SJ, Chung SS, Rho EJ et al (2006) Negative modulation of RXRalpha transcriptional activity by small ubiquitin-related modifier (SUMO) modification and its reversal by SUMO-specific protease SUSP1. J Biol Chem 281:30669–30677

    Article  CAS  PubMed  Google Scholar 

  214. Kho C, Lee A, Jeong D et al (2011) SUMO1-dependent modulation of SERCA2a in heart failure. Nature 477:601–605

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  215. Lin X, Liang M, Liang YY et al (2003) SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4. J Biol Chem 278:31043–31048

    Article  CAS  PubMed  Google Scholar 

  216. Lin X, Liang M, Liang YY et al (2003) Activation of transforming growth factor-beta signaling by SUMO-1 modification of tumor suppressor Smad4/DPC4. J Biol Chem 278:18714–18719

    Article  CAS  PubMed  Google Scholar 

  217. Long J, Wang G, He D et al (2004) Repression of Smad4 transcriptional activity by SUMO modification. Biochem J 379:23–29

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  218. Matsuzaki K, Minami T, Tojo M et al (2003) Serum response factor is modulated by the SUMO-1 conjugation system. Biochem Biophys Res Commun 306:32–38

    Article  CAS  PubMed  Google Scholar 

  219. Beketaev I, Kim EY, Zhang Y et al (2014) Potentiation of Tbx5-mediated transactivation by SUMO conjugation and protein inhibitor of activated STAT 1 (PIAS1). Int J Biochem Cell Biol 50:82–92

    Article  CAS  PubMed  Google Scholar 

  220. Kruse M, Schulze-Bahr E, Corfield V et al (2009) Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest 119:2737–2744

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  221. Chen L, Ma Y, Qian L et al (2013) Sumoylation regulates nuclear localization and function of zinc finger transcription factor ZIC3. Biochim Biophys Acta 1833:2725–2733

    Article  CAS  PubMed  Google Scholar 

  222. Costa MW, Lee S, Furtado MB et al (2011) Complex SUMO-1 regulation of cardiac transcription factor Nkx2-5. PLoS One 6, e24812

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  223. Alkuraya FS, Saadi I, Lund JJ et al (2006) SUMO1 haploinsufficiency leads to cleft lip and palate. Science 313:1751

    Article  PubMed  Google Scholar 

  224. Wang J, Chen L, Wen S et al (2011) Defective sumoylation pathway directs congenital heart disease. Birth Defects Res A Clin Mol Teratol 91:468–476

    Article  CAS  PubMed  Google Scholar 

  225. Zhang FP, Mikkonen L, Toppari J et al (2008) Sumo-1 function is dispensable in normal mouse development. Mol Cell Biol 28:5381–5390

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  226. Evdokimov E, Sharma P, Lockett SJ et al (2008) Loss of SUMO1 in mice affects RanGAP1 localization and formation of PML nuclear bodies, but is not lethal as it can be compensated by SUMO2 or SUMO3. J Cell Sci 121:4106–4113

    Article  CAS  PubMed  Google Scholar 

  227. Kim EY, Chen L, Ma Y et al (2012) Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction. J Mol Cell Cardiol 52:638–649

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  228. Kim EY, Chen L, Ma Y et al (2011) Expression of sumoylation deficient Nkx2.5 mutant in Nkx2.5 haploinsufficient mice leads to congenital heart defects. PLoS One 6, e20803

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  229. van Tintelen JP, van Spaendonck-Zwarts KY, van den Berg MP (2010) Lamin A/C-related cardiac disease and pregnancy. Eur J Heart Fail 12:532–534

    Article  PubMed  CAS  Google Scholar 

  230. Fatkin D, MacRae C, Sasaki T et al (1999) Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 341:1715–1724

    Article  CAS  PubMed  Google Scholar 

  231. Jakobs PM, Hanson EL, Crispell KA et al (2001) Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease. J Card Fail 7:249–256

    Article  CAS  PubMed  Google Scholar 

  232. Tilemann L, Lee A, Ishikawa K et al (2013) SUMO-1 gene transfer improves cardiac function in a large-animal model of heart failure. Sci Transl Med 5:211ra159

    Article  PubMed  CAS  Google Scholar 

  233. Kim EY, Zhang Y, Beketaev I et al (2015) SENP5, a SUMO isopeptidase, induces apoptosis and cardiomyopathy. J Mol Cell Cardiol 78:154–164

    Article  CAS  PubMed  Google Scholar 

  234. Brink PA, Ferreira A, Moolman JC et al (1995) Gene for progressive familial heart block type I maps to chromosome 19q13. Circulation 91:1633–1640

    Article  CAS  PubMed  Google Scholar 

  235. Liu H, El Zein L, Kruse M et al (2010) Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease. Circ Cardiovasc Genet 3:374–385

    Article  CAS  PubMed  Google Scholar 

  236. Dai XQ, Kolic J, Marchi P et al (2009) SUMOylation regulates Kv2.1 and modulates pancreatic beta-cell excitability. J Cell Sci 122:775–779

    Article  CAS  PubMed  Google Scholar 

  237. Benson MD, Li QJ, Kieckhafer K et al (2007) SUMO modification regulates inactivation of the voltage-gated potassium channel Kv1.5. Proc Natl Acad Sci U S A 104:1805–1810

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  238. Lee YJ, Mou Y, Maric D et al (2011) Elevated global SUMOylation in Ubc9 transgenic mice protects their brains against focal cerebral ischemic damage. PLoS One 6, e25852

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  239. Lee YJ, Miyake S, Wakita H et al (2007) Protein SUMOylation is massively increased in hibernation torpor and is critical for the cytoprotection provided by ischemic preconditioning and hypothermia in SHSY5Y cells. J Cereb Blood Flow Metab 27:950–962

    CAS  PubMed Central  PubMed  Google Scholar 

  240. Cimarosti H, Lindberg C, Bomholt SF et al (2008) Increased protein SUMOylation following focal cerebral ischemia. Neuropharmacology 54:280–289

    Article  CAS  PubMed  Google Scholar 

  241. Yang W, Sheng H, Warner DS et al (2008) Transient global cerebral ischemia induces a massive increase in protein sumoylation. J Cereb Blood Flow Metab 28:269–279

    Article  PubMed  CAS  Google Scholar 

  242. Shao R, Zhang FP, Tian F et al (2004) Increase of SUMO-1 expression in response to hypoxia: direct interaction with HIF-1alpha in adult mouse brain and heart in vivo. FEBS Lett 569:293–300

    Article  CAS  PubMed  Google Scholar 

  243. Shishido T, Woo CH, Ding B et al (2008) Effects of MEK5/ERK5 association on small ubiquitin-related modification of ERK5: implications for diabetic ventricular dysfunction after myocardial infarction. Circ Res 102:1416–1425

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  244. Carbia-Nagashima A, Gerez J, Perez-Castro C et al (2007) RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia. Cell 131:309–323

    Article  CAS  PubMed  Google Scholar 

  245. Berta MA, Mazure N, Hattab M et al (2007) SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional activity. Biochem Biophys Res Commun 360:646–652

    Article  CAS  PubMed  Google Scholar 

  246. Bae SH, Jeong JW, Park JA et al (2004) Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem Biophys Res Commun 324:394–400

    Article  CAS  PubMed  Google Scholar 

  247. Huang RY, Kowalski D, Minderman H et al (2007) Small ubiquitin-related modifier pathway is a major determinant of doxorubicin cytotoxicity in Saccharomyces cerevisiae. Cancer Res 67:765–772

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work from the authors’ lab was supported by the grants from the Texas Higher Education Coordinating Board (THECB), the American Heart Association, and the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Stem Cell Engineering, Texas Heart Institute, Houston, TX, USA

    Jun Wang & Robert J. Schwartz

  2. Department of Biochemistry and Molecular Biology, University of Houston, Houston, TX, USA

    Robert J. Schwartz

Authors
  1. Jun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert J. Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jun Wang or Robert J. Schwartz .

Editor information

Editors and Affiliations

  1. Cardiovascular Genetics, Charité - Universitätsmedizin Berlin , Berlin, Germany

    Silke Rickert-Sperling

  2. Developmental Biology, Inst. of Marseilles, Aix-Marseille Univ. , Marseille, France

    Robert G. Kelly

  3. Dpt. of Pediatrics Div.of Pediatric Card, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    David J. Driscoll

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer-Verlag Wien

About this chapter

Cite this chapter

Wang, J., Schwartz, R.J. (2016). Post-translational Modification. In: Rickert-Sperling, S., Kelly, R., Driscoll, D. (eds) Congenital Heart Diseases: The Broken Heart. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1883-2_14

Download citation

Publish with us

Policies and ethics

Search

Navigation