Advertisement

Protein Degradation in Cardiomyocytes: Target Proteins and Clinical Consequences

  • Oliver DrewsEmail author
Chapter

Abstract

Protein degradation or proteolysis is casually considered an uneventful process of decomposition and hence its role in health and disease underestimated. Current understanding though describes proteolysis as part of versatile and dynamic signalling networks, encompassing hundreds, potentially more than a thousand, of proteins. Proteolytic events are adjusted in response to physiological stimuli and in turn have the capacity to alter cellular as well as systemic function. Similarly, controlled protein degradation influences the pathophysiology with dysregulated or insufficient proteolysis considered driving disease progression, or even being part of early pathophysiological development. Therefore, a rapidly increasing number of studies incorporate involvement of proteolytic regulation in their hypothesis. Our view of proteolytic regulation via autophagy and the ubiquitin-proteasome pathway in particular evolved to the level that they are considered decisive in disease development. Indeed, their manipulation in vitro as well as in vivo influence cardiomyocyte function and cardiac disease outcome. Substrates subject to degradation range from single proteins (ubiquitin-proteasome pathway) to complete organelles (autophagy). In this chapter, protein degradation via the UPS and autophagy are discussed within the context of physiological function and pathophysiological impact.

Keywords

H9c2 Cell Proteasome Activity Autophagic Vacuole Autophagic Flux Ischaemic Precondition 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Aki T, Yamaguchi K, Fujimiya T, Mizukami Y (2003) Phosphoinositide 3-kinase accelerates autophagic cell death during glucose deprivation in the rat cardiomyocyte-derived cell line H9c2. Oncogene 22:8529–8535PubMedCrossRefGoogle Scholar
  2. Alves-Rodrigues A, Gregori L, Figueiredo-Pereira ME (1998) Ubiquitin, cellular inclusions and their role in neurodegeneration. Trends Neurosci 21:516–520PubMedCrossRefGoogle Scholar
  3. Angeles A, Fung G, Luo H (2012) Immune and non-immune functions of the immunoproteasome. Front Biosci (Landmark Ed) 17:1904–1916CrossRefGoogle Scholar
  4. Appelqvist H, Waster P, Kagedal K, Ollinger K (2013) The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol 5:214–226PubMedCrossRefGoogle Scholar
  5. Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Furst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Hohfeld J (2010) Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol CB 20:143–148PubMedCrossRefGoogle Scholar
  6. Arya R, Kedar V, Hwang JR, McDonough H, Li HH, Taylor J, Patterson C (2004) Muscle ring finger protein-1 inhibits PKC{epsilon} activation and prevents cardiomyocyte hypertrophy. J Cell Biol 167:1147–1159PubMedPubMedCentralCrossRefGoogle Scholar
  7. Asai M, Tsukamoto O, Minamino T, Asanuma H, Fujita M, Asano Y, Takahama H, Sasaki H, Higo S, Asakura M, Takashima S, Hori M, Kitakaze M (2009) PKA rapidly enhances proteasome assembly and activity in in vivo canine hearts. J Mol Cell Cardiol 46:452–462PubMedCrossRefGoogle Scholar
  8. Bahro M, Pfeifer U (1987) Short-term stimulation by propranolol and verapamil of cardiac cellular autophagy. J Mol Cell Cardiol 19:1169–1178PubMedCrossRefGoogle Scholar
  9. Bahrudin U, Morisaki H, Morisaki T, Ninomiya H, Higaki K, Nanba E, Igawa O, Takashima S, Mizuta E, Miake J, Yamamoto Y, Shirayoshi Y, Kitakaze M, Carrier L, Hisatome I (2008) Ubiquitin-proteasome system impairment caused by a missense cardiac myosin-binding protein C mutation and associated with cardiac dysfunction in hypertrophic cardiomyopathy. J Mol Biol 384:896–907PubMedCrossRefGoogle Scholar
  10. Baskin KK, Rodriguez MR, Kansara S, Chen W, Carranza S, Frazier OH, Glass DJ, Taegtmeyer H (2014) MAFbx/Atrogin-1 is required for atrophic remodeling of the unloaded heart. J Mol Cell Cardiol 72:168–176PubMedPubMedCentralCrossRefGoogle Scholar
  11. Basler M, Kirk CJ, Groettrup M (2013) The immunoproteasome in antigen processing and other immunological functions. Curr Opin Immunol 25:74–80PubMedCrossRefGoogle Scholar
  12. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555PubMedCrossRefGoogle Scholar
  13. Bhuiyan MS, Pattison JS, Osinska H, James J, Gulick J, McLendon PM, Hill JA, Sadoshima J, Robbins J (2013) Enhanced autophagy ameliorates cardiac proteinopathy. J Clin Invest 123:5284–5297PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bonifacino JS, Traub LM (2003) Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 72:395–447PubMedCrossRefGoogle Scholar
  15. Bose S, Brooks P, Mason GG, Rivett AJ (2001) Gamma-interferon decreases the level of 26 S proteasomes and changes the pattern of phosphorylation. Biochem J 353:291–297PubMedPubMedCentralGoogle Scholar
  16. Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27:6434–6451PubMedCrossRefGoogle Scholar
  17. Braunwald E (2008) Biomarkers in heart failure. N Engl J Med 358:2148–2159PubMedCrossRefGoogle Scholar
  18. Bulteau AL, Lundberg KC, Humphries KM, Sadek HA, Szweda PA, Friguet B, Szweda LI (2001) Oxidative modification and inactivation of the proteasome during coronary occlusion/reperfusion. J Biol Chem 276:30057–30063PubMedCrossRefGoogle Scholar
  19. Calise J, Powell SR (2012) The ubiquitin proteasome system and myocardial ischemia. Am J Physiol Heart Circ Physiol 304:H337–H349PubMedPubMedCentralCrossRefGoogle Scholar
  20. Campbell B, Adams J, Shin YK, Lefer AM (1999) Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart. J Mol Cell Cardiol 31:467–476PubMedCrossRefGoogle Scholar
  21. Churchill EN, Ferreira JC, Brum PC, Szweda LI, Mochly-Rosen D (2010) Ischaemic preconditioning improves proteasomal activity and increases the degradation of deltaPKC during reperfusion. Cardiovasc Res 85:385–394PubMedCrossRefGoogle Scholar
  22. Cui Z, Scruggs SB, Gilda JE, Ping P, Gomes AV (2014) Regulation of cardiac proteasomes by ubiquitination, SUMOylation, and beyond. J Mol Cell Cardiol 71:32–34PubMedCrossRefGoogle Scholar
  23. Dahlmann B, Becher B, Sobek A, Ehlers C, Kopp F, Kuehn L (1993) In vitro activation of the 20S proteasome. Enzyme Protein 47:274–284PubMedGoogle Scholar
  24. Dai DF, Chen T, Johnson SC, Szeto H, Rabinovitch PS (2012) Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal 16:1492–1526PubMedPubMedCentralCrossRefGoogle Scholar
  25. Dantuma NP, Lindsten K, Glas R, Jellne M, Masucci MG (2000) Short-lived green fluorescent proteins for quantifying ubiquitin/proteasome-dependent proteolysis in living cells. Nat Biotechnol 18:538–543PubMedCrossRefGoogle Scholar
  26. Day SM, Divald A, Wang P, Davis F, Bartolone S, Jones R, Powell SR (2013) Impaired assembly and post-translational regulation of 26S proteasome in human end-stage heart failure. Circ Heart Fail 6:544–549PubMedCrossRefGoogle Scholar
  27. Decker RS, Wildenthal K (1980) Lysosomal alterations in hypoxic and reoxygenated hearts. I. Ultrastructural and cytochemical changes. Am J Pathol 98:425–444PubMedPubMedCentralGoogle Scholar
  28. Depre C, Wang Q, Yan L, Hedhli N, Peter P, Chen L, Hong C, Hittinger L, Ghaleh B, Sadoshima J, Vatner DE, Vatner SF, Madura K (2006) Activation of the cardiac proteasome during pressure overload promotes ventricular hypertrophy. Circulation 114:1821–1828PubMedCrossRefGoogle Scholar
  29. Divald A, Powell SR (2006) Proteasome mediates removal of proteins oxidized during myocardial ischemia. Free Radic Biol Med 40:156–164PubMedCrossRefGoogle Scholar
  30. Divald A, Kivity S, Wang P, Hochhauser E, Roberts B, Teichberg S, Gomes AV, Powell SR (2010) Myocardial ischemic preconditioning preserves postischemic function of the 26S proteasome through diminished oxidative damage to 19S regulatory particle subunits. Circ Res 106:1829–1838PubMedCrossRefGoogle Scholar
  31. Dores MR, Trejo J (2012) Ubiquitination of G protein-coupled receptors: functional implications and drug discovery. Mol Pharmacol 82:563–570PubMedPubMedCentralCrossRefGoogle Scholar
  32. Drews O (2014) The left and right ventricle in the grip of protein degradation: similarities and unique patterns in regulation. J Mol Cell Cardiol 72:52–55PubMedCrossRefGoogle Scholar
  33. Drews O, Taegtmeyer H (2014) Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies. Antioxid Redox Signal 21:2322–2343PubMedPubMedCentralCrossRefGoogle Scholar
  34. Drews O, Wildgruber R, Zong C, Sukop U, Nissum M, Weber G, Gomes AV, Ping P (2007a) Mammalian proteasome subpopulations with distinct molecular compositions and proteolytic activities. Mol Cell Proteomics 6:2021–2031PubMedCrossRefGoogle Scholar
  35. Drews O, Zong C, Ping P (2007b) Exploring proteasome complexes by proteomic approaches. Proteomics 7:1047–1058PubMedCrossRefGoogle Scholar
  36. Drews O, Tsukamoto O, Liem D, Streicher J, Wang Y, Ping P (2010) Differential regulation of proteasome function in isoproterenol-induced cardiac hypertrophy. Circ Res 107:1094–1101PubMedPubMedCentralCrossRefGoogle Scholar
  37. Elsasser A, Vogt AM, Nef H, Kostin S, Mollmann H, Skwara W, Bode C, Hamm C, Schaper J (2004) Human hibernating myocardium is jeopardized by apoptotic and autophagic cell death. J Am Coll Cardiol 43:2191–2199PubMedCrossRefGoogle Scholar
  38. Farout L, Friguet B (2006) Proteasome function in aging and oxidative stress: implications in protein maintenance failure. Antioxid Redox Signal 8:205–216PubMedCrossRefGoogle Scholar
  39. Fielitz J, Kim MS, Shelton JM, Latif S, Spencer JA, Glass DJ, Richardson JA, Bassel-Duby R, Olson EN (2007) Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3. J Clin Invest 117:2486–2495PubMedPubMedCentralCrossRefGoogle Scholar
  40. Finley D (2009) Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu Rev Biochem 78:477–513PubMedPubMedCentralCrossRefGoogle Scholar
  41. Gaczynska M, Osmulski PA (2014) Harnessing proteasome dynamics and allostery in drug design. Antioxid Redox Signal 21:2286–2301PubMedPubMedCentralCrossRefGoogle Scholar
  42. Gaczynska M, Rock KL, Spies T, Goldberg AL (1994) Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7. Proc Natl Acad Sci U S A 91:9213–9217PubMedPubMedCentralCrossRefGoogle Scholar
  43. Gaczynska M, Goldberg AL, Tanaka K, Hendil KB, Rock KL (1996) Proteasome subunits X and Y alter peptidase activities in opposite ways to the interferon-gamma-induced subunits LMP2 and LMP7. J Biol Chem 271:17275–17280PubMedCrossRefGoogle Scholar
  44. Gilon T, Chomsky O, Kulka RG (1998) Degradation signals for ubiquitin system proteolysis in saccharomyces cerevisiae. EMBO J 17:2759–2766PubMedPubMedCentralCrossRefGoogle Scholar
  45. Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428PubMedCrossRefGoogle Scholar
  46. Goldberg AL, Rock KL (1992) Proteolysis, proteasomes and antigen presentation. Nature 357:375–379PubMedCrossRefGoogle Scholar
  47. Goldfarb LG, Dalakas MC (2009) Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. J Clin Invest 119:1806–1813PubMedPubMedCentralCrossRefGoogle Scholar
  48. Gomes AV, Zong C, Edmondson RD, Li X, Stefani E, Zhang J, Jones RC, Thyparambil S, Wang GW, Qiao X, Bardag-Gorce F, Ping P (2006) Mapping the murine cardiac 26S proteasome complexes. Circ Res 99:362–371PubMedCrossRefGoogle Scholar
  49. Gomes AV, Young GW, Wang Y, Zong C, Eghbali M, Drews O, Lu H, Stefani E, Ping P (2009) Contrasting proteome biology and functional heterogeneity of the 20 S proteasome complexes in mammalian tissues. Mol Cell Proteomics 8:302–315PubMedPubMedCentralCrossRefGoogle Scholar
  50. Groll M, Huber R (2004) Inhibitors of the eukaryotic 20S proteasome core particle: a structural approach. Biochim Biophys Acta 1695:33–44PubMedCrossRefGoogle Scholar
  51. Groll M, Heinemeyer W, Jager S, Ullrich T, Bochtler M, Wolf DH, Huber R (1999) The catalytic sites of 20S proteasomes and their role in subunit maturation: a mutational and crystallographic study. Proc Natl Acad Sci U S A 96:10976–10983PubMedPubMedCentralCrossRefGoogle Scholar
  52. Groll M, Bajorek M, Kohler A, Moroder L, Rubin DM, Huber R, Glickman MH, Finley D (2000) A gated channel into the proteasome core particle. Nat Struct Biol 7:1062–1067PubMedCrossRefGoogle Scholar
  53. Grune T, Reinheckel T, Davies KJ (1997) Degradation of oxidized proteins in mammalian cells. FASEB J 11:526–534PubMedGoogle Scholar
  54. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V (2004) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119:753–766PubMedCrossRefGoogle Scholar
  55. Hamacher-Brady A, Brady NR, Gottlieb RA (2006) Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 281:29776–29787PubMedCrossRefGoogle Scholar
  56. Hanna RA, Quinsay MN, Orogo AM, Giang K, Rikka S, Gustafsson AB (2012) Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J Biol Chem 287:19094–19104PubMedPubMedCentralCrossRefGoogle Scholar
  57. Hedhli N, Lizano P, Hong C, Fritzky LF, Dhar SK, Liu H, Tian Y, Gao S, Madura K, Vatner SF, Depre C (2008) Proteasome inhibition decreases cardiac remodeling after initiation of pressure overload. Am J Physiol Heart Circ Physiol 295:H1385–H1393PubMedPubMedCentralCrossRefGoogle Scholar
  58. Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, Bauer EP, Klovekorn WP, Schaper J (2003) Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation 107:984–991PubMedCrossRefGoogle Scholar
  59. Herndon T, Deisseroth AB, Kaminskas E, Kane RC, Koti KM, Rothmann MD, Habtemariam BA, Bullock J, Bray JD, Hawes JH, Palmby TR, Jee J, Adams WM, Mahayni H, Brown J, Dorantes A, Sridhara R, Farrell AT, Pazdur R (2013) U.S. food and drug administration approval: carfilzomib for the treatment of multiple myeloma. Clin Cancer Res 19:4559–4563PubMedCrossRefGoogle Scholar
  60. Herrmann J, Wohlert C, Saguner AM, Flores A, Nesbitt LL, Chade A, Lerman LO, Lerman A (2013) Primary proteasome inhibition results in cardiac dysfunction. Eur J Heart Fail 15:614–623PubMedPubMedCentralCrossRefGoogle Scholar
  61. Hu RG, Sheng J, Qi X, Xu Z, Takahashi TT, Varshavsky A (2005) The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators. Nature 437:981–986PubMedCrossRefGoogle Scholar
  62. Huang S, Patterson E, Yu X, Garrett MW, De Aos I, Kem DC (2008) Proteasome inhibition 1 h following ischemia protects GRK2 and prevents malignant ventricular tachyarrhythmias and SCD in a model of myocardial infarction. Am J Physiol Heart Circ Physiol 294:H1298–H1303PubMedCrossRefGoogle Scholar
  63. Huber EM, Basler M, Schwab R, Heinemeyer W, Kirk CJ, Groettrup M, Groll M (2012) Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity. Cell 148:727–738PubMedCrossRefGoogle Scholar
  64. Hunter JJ, Chien KR (1999) Signaling pathways for cardiac hypertrophy and failure. N Engl J Med 341:1276–1283PubMedCrossRefGoogle Scholar
  65. Kane RC, Bross PF, Farrell AT, Pazdur R (2003) Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 8:508–513PubMedCrossRefGoogle Scholar
  66. Kassiotis C, Ballal K, Wellnitz K, Vela D, Gong M, Salazar R, Frazier OH, Taegtmeyer H (2009) Markers of autophagy are downregulated in failing human heart after mechanical unloading. Circulation 120:S191–S197PubMedPubMedCentralCrossRefGoogle Scholar
  67. Kedar V, McDonough H, Arya R, Li HH, Rockman HA, Patterson C (2004) Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I. Proc Natl Acad Sci U S A 101:18135–18140PubMedPubMedCentralCrossRefGoogle Scholar
  68. Kim YC, Guan KL (2015) mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 125:25–32PubMedPubMedCentralCrossRefGoogle Scholar
  69. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141PubMedPubMedCentralCrossRefGoogle Scholar
  70. Kirkin V, Lamark T, Sou YS, Bjorkoy G, Nunn JL, Bruun JA, Shvets E, McEwan DG, Clausen TH, Wild P, Bilusic I, Theurillat JP, Overvatn A, Ishii T, Elazar Z, Komatsu M, Dikic I, Johansen T (2009) A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell 33:505–516PubMedCrossRefGoogle Scholar
  71. Kisselev AF, Goldberg AL (2001) Proteasome inhibitors: from research tools to drug candidates. Chem Biol 8:739–758PubMedCrossRefGoogle Scholar
  72. Kisselev AF, Akopian TN, Woo KM, Goldberg AL (1999) The sizes of peptides generated from protein by mammalian 26 and 20 S proteasomes. Implications for understanding the degradative mechanism and antigen presentation. J Biol Chem 274:3363–3371PubMedCrossRefGoogle Scholar
  73. Kisselev AF, van der Linden WA, Overkleeft HS (2012) Proteasome inhibitors: an expanding army attacking a unique target. Chem Biol 19:99–115PubMedPubMedCentralCrossRefGoogle Scholar
  74. Kloss A, Meiners S, Ludwig A, Dahlmann B (2010) Multiple cardiac proteasome subtypes differ in their susceptibility to proteasome inhibitors. Cardiovasc Res 85:367–375PubMedCrossRefGoogle Scholar
  75. Knaapen MW, Davies MJ, De Bie M, Haven AJ, Martinet W, Kockx MM (2001) Apoptotic versus autophagic cell death in heart failure. Cardiovasc Res 51:304–312PubMedCrossRefGoogle Scholar
  76. Koitabashi N, Kass DA (2011) Reverse remodeling in heart failure – mechanisms and therapeutic opportunities. Nat Rev Cardiol 9:147–157PubMedCrossRefGoogle Scholar
  77. Kostin S, Pool L, Elsasser A, Hein S, Drexler HC, Arnon E, Hayakawa Y, Zimmermann R, Bauer E, Klovekorn WP, Schaper J (2003) Myocytes die by multiple mechanisms in failing human hearts. Circ Res 92:715–724PubMedCrossRefGoogle Scholar
  78. Kruger E, Kloetzel PM (2012) Immunoproteasomes at the interface of innate and adaptive immune responses: two faces of one enzyme. Curr Opin Immunol 24:77–83PubMedCrossRefGoogle Scholar
  79. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036PubMedCrossRefGoogle Scholar
  80. Kumarapeli AR, Horak KM, Glasford JW, Li J, Chen Q, Liu J, Zheng H, Wang X (2005) A novel transgenic mouse model reveals deregulation of the ubiquitin-proteasome system in the heart by doxorubicin. FASEB J 19:2051–2053PubMedGoogle Scholar
  81. Lam YA, Lawson TG, Velayutham M, Zweier JL, Pickart CM (2002) A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal. Nature 416:763–767PubMedCrossRefGoogle Scholar
  82. Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122:3589–3594PubMedPubMedCentralCrossRefGoogle Scholar
  83. Lefkowitz RJ, Rockman HA, Koch WJ (2000) Catecholamines, cardiac beta-adrenergic receptors, and heart failure. Circulation 101:1634–1637PubMedCrossRefGoogle Scholar
  84. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42PubMedPubMedCentralCrossRefGoogle Scholar
  85. Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115:2679–2688PubMedPubMedCentralCrossRefGoogle Scholar
  86. Li HH, Kedar V, Zhang C, McDonough H, Arya R, Wang DZ, Patterson C (2004) Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. J Clin Invest 114:1058–1071PubMedPubMedCentralCrossRefGoogle Scholar
  87. Li HH, Willis MS, Lockyer P, Miller N, McDonough H, Glass DJ, Patterson C (2007) Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins. J Clin Invest 117:3211–3223PubMedPubMedCentralCrossRefGoogle Scholar
  88. Li J, Horak KM, Su H, Sanbe A, Robbins J, Wang X (2011a) Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice. J Clin Invest 121:3689–3700PubMedPubMedCentralCrossRefGoogle Scholar
  89. Li J, Powell SR, Wang X (2011b) Enhancement of proteasome function by PA28α overexpression protects against oxidative stress. FASEB J 25:883–893PubMedPubMedCentralCrossRefGoogle Scholar
  90. Link CD, Fonte V, Hiester B, Yerg J, Ferguson J, Csontos S, Silverman MA, Stein GH (2006) Conversion of green fluorescent protein into a toxic, aggregation-prone protein by C-terminal addition of a short peptide. J Biol Chem 281:1808–1816PubMedCrossRefGoogle Scholar
  91. Liu J, Tang M, Mestril R, Wang X (2006) Aberrant protein aggregation is essential for a mutant desmin to impair the proteolytic function of the ubiquitin-proteasome system in cardiomyocytes. J Mol Cell Cardiol 40:451–454PubMedCrossRefGoogle Scholar
  92. Lohse MJ, Engelhardt S, Eschenhagen T (2003) What is the role of beta-adrenergic signaling in heart failure? Circ Res 93:896–906PubMedCrossRefGoogle Scholar
  93. Lu H, Zong C, Wang Y, Young GW, Deng N, Souda P, Li X, Whitelegge J, Drews O, Yang PY, Ping P (2008) Revealing the dynamics of the 20 S proteasome phosphoproteome: a combined CID and electron transfer dissociation approach. Mol Cell Proteomics 7:2073–2089PubMedPubMedCentralCrossRefGoogle Scholar
  94. Mason GG, Hendil KB, Rivett AJ (1996) Phosphorylation of proteasomes in mammalian cells. Identification of two phosphorylated subunits and the effect of phosphorylation on activity. Eur J Biochem 238:453–462PubMedCrossRefGoogle Scholar
  95. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100:914–922PubMedCrossRefGoogle Scholar
  96. McLendon PM, Robbins J (2011) Desmin-related cardiomyopathy: an unfolding story. Am J Physiol Heart Circ Physiol 301:H1220–H1228PubMedPubMedCentralCrossRefGoogle Scholar
  97. McMullen JR, Sherwood MC, Tarnavski O, Zhang L, Dorfman AL, Shioi T, Izumo S (2004) Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109:3050–3055PubMedCrossRefGoogle Scholar
  98. Miyata S, Minobe W, Bristow MR, Leinwand LA (2000) Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res 86:386–390PubMedCrossRefGoogle Scholar
  99. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15:1101–1111PubMedPubMedCentralCrossRefGoogle Scholar
  100. Mizushima N, Yoshimori T, Levine B (2010) Methods in mammalian autophagy research. Cell 140:313–326PubMedPubMedCentralCrossRefGoogle Scholar
  101. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, Omiya S, Mizote I, Matsumura Y, Asahi M, Nishida K, Hori M, Mizushima N, Otsu K (2007) The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13:619–624PubMedCrossRefGoogle Scholar
  102. Nathan JA, Spinnenhirn V, Schmidtke G, Basler M, Groettrup M, Goldberg AL (2013) Immuno- and constitutive proteasomes do not differ in their abilities to degrade ubiquitinated proteins. Cell 152:1184–1194PubMedPubMedCentralCrossRefGoogle Scholar
  103. Naviglio S, Pagano M, Romano M, Sorrentino A, Fusco A, Illiano F, Chiosi E, Spina A, Illiano G (2004) Adenylate cyclase regulation via proteasome-mediated modulation of Galphas levels. Cell Signal 16:1229–1237PubMedCrossRefGoogle Scholar
  104. Nishino I, Fu J, Tanji K, Yamada T, Shimojo S, Koori T, Mora M, Riggs JE, Oh SJ, Koga Y, Sue CM, Yamamoto A, Murakami N, Shanske S, Byrne E, Bonilla E, Nonaka I, DiMauro S, Hirano M (2000) Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406:906–910PubMedCrossRefGoogle Scholar
  105. Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, Rogov V, Lohr F, Popovic D, Occhipinti A, Reichert AS, Terzic J, Dotsch V, Ney PA, Dikic I (2010) Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep 11:45–51PubMedCrossRefGoogle Scholar
  106. Opitz E, Koch A, Klingel K, Schmidt F, Prokop S, Rahnefeld A, Sauter M, Heppner FL, Volker U, Kandolf R, Kuckelkorn U, Stangl K, Kruger E, Kloetzel PM, Voigt A (2011) Impairment of immunoproteasome function by beta5i/LMP7 subunit deficiency results in severe enterovirus myocarditis. PLoS Pathog 7:e1002233PubMedPubMedCentralCrossRefGoogle Scholar
  107. Orino E, Tanaka K, Tamura T, Sone S, Ogura T, Ichihara A (1991) ATP-dependent reversible association of proteasomes with multiple protein components to form 26S complexes that degrade ubiquitinated proteins in human HL-60 cells. FEBS Lett 284:206–210PubMedCrossRefGoogle Scholar
  108. Pagan J, Seto T, Pagano M, Cittadini A (2013) Role of the ubiquitin proteasome system in the heart. Circ Res 112:1046–1058PubMedCrossRefGoogle Scholar
  109. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282:24131–24145PubMedCrossRefGoogle Scholar
  110. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939PubMedCrossRefGoogle Scholar
  111. Pattison JS, Osinska H, Robbins J (2011) Atg7 induces basal autophagy and rescues autophagic deficiency in CryABR120G cardiomyocytes. Circ Res 109:151–160PubMedPubMedCentralCrossRefGoogle Scholar
  112. Peters JM, Cejka Z, Harris JR, Kleinschmidt JA, Baumeister W (1993) Structural features of the 26 S proteasome complex. J Mol Biol 234:932–937PubMedCrossRefGoogle Scholar
  113. Peters JM, Franke WW, Kleinschmidt JA (1994) Distinct 19 S and 20 S subcomplexes of the 26 S proteasome and their distribution in the nucleus and the cytoplasm. J Biol Chem 269:7709–7718PubMedGoogle Scholar
  114. Pfeifer U, Fohr J, Wilhelm W, Dammrich J (1987) Short-term inhibition of cardiac cellular autophagy by isoproterenol. J Mol Cell Cardiol 19:1179–1184PubMedCrossRefGoogle Scholar
  115. Powell SR, Divald A (2010) The ubiquitin-proteasome system in myocardial ischaemia and preconditioning. Cardiovasc Res 85:303–311PubMedCrossRefGoogle Scholar
  116. Powell SR, Wang P, Katzeff H, Shringarpure R, Teoh C, Khaliulin I, Das DK, Davies KJ, Schwalb H (2005) Oxidized and ubiquitinated proteins may predict recovery of postischemic cardiac function: essential role of the proteasome. Antioxid Redox Signal 7:538–546PubMedCrossRefGoogle Scholar
  117. Powell SR, Davies KJ, Divald A (2007) Optimal determination of heart tissue 26S-proteasome activity requires maximal stimulating ATP concentrations. J Mol Cell Cardiol 42:265–269PubMedCrossRefGoogle Scholar
  118. Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM (2010) Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies. Circulation 121:997–1004PubMedPubMedCentralCrossRefGoogle Scholar
  119. Priault M, Salin B, Schaeffer J, Vallette FM, di Rago JP, Martinou JC (2005) Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast. Cell Death Differ 12:1613–1621PubMedCrossRefGoogle Scholar
  120. Ranek MJ, Terpstra EJ, Li J, Kass DA, Wang X (2013) Protein kinase G positively regulates proteasome-mediated degradation of misfolded proteins. Circulation 128:365–376PubMedPubMedCentralCrossRefGoogle Scholar
  121. Ranek MJ, Zheng H, Huang W, Kumarapeli AR, Li J, Liu J, Wang X (2015) Genetically induced moderate inhibition of 20S proteasomes in cardiomyocytes facilitates heart failure in mice during systolic overload. J Mol Cell Cardiol 85:273–281PubMedCrossRefGoogle Scholar
  122. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O’Kane CJ, Rubinsztein DC (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595PubMedCrossRefGoogle Scholar
  123. Rivett AJ (1989) The multicatalytic proteinase. Multiple proteolytic activities. J Biol Chem 264:12215–12219PubMedGoogle Scholar
  124. Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D, Goldberg AL (1994) Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78:761–771PubMedCrossRefGoogle Scholar
  125. Rockman HA, Koch WJ, Lefkowitz RJ (2002) Seven-transmembrane-spanning receptors and heart function. Nature 415:206–212PubMedCrossRefGoogle Scholar
  126. Salcedo A, Mayor F Jr, Penela P (2006) Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2. EMBO J 25:4752–4762PubMedPubMedCentralCrossRefGoogle Scholar
  127. Sandri M, Robbins J (2013) Proteotoxicity: an underappreciated pathology in cardiac disease. J Mol Cell Cardiol 71C:3–10Google Scholar
  128. Sarikas A, Carrier L, Schenke C, Doll D, Flavigny J, Lindenberg KS, Eschenhagen T, Zolk O (2005) Impairment of the ubiquitin-proteasome system by truncated cardiac myosin binding protein C mutants. Cardiovasc Res 66:33–44PubMedCrossRefGoogle Scholar
  129. Satoh K, Sasajima H, Nyoumura KI, Yokosawa H, Sawada H (2001) Assembly of the 26S proteasome is regulated by phosphorylation of the p45/Rpt6 ATPase subunit. Biochemistry 40:314–319PubMedCrossRefGoogle Scholar
  130. Schlossarek S, Mearini G, Carrier L (2011) Cardiac myosin-binding protein C in hypertrophic cardiomyopathy: mechanisms and therapeutic opportunities. J Mol Cell Cardiol 50:613–620PubMedCrossRefGoogle Scholar
  131. Schlossarek S, Frey N, Carrier L (2014) Ubiquitin-proteasome system and hereditary cardiomyopathies. J Mol Cell Cardiol 71:25–31PubMedCrossRefGoogle Scholar
  132. Seifert U, Bialy LP, Ebstein F, Bech-Otschir D, Voigt A, Schroter F, Prozorovski T, Lange N, Steffen J, Rieger M, Kuckelkorn U, Aktas O, Kloetzel PM, Kruger E (2010) Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142:613–624PubMedCrossRefGoogle Scholar
  133. Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408PubMedPubMedCentralCrossRefGoogle Scholar
  134. Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ (2001) Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294:1307–1313PubMedCrossRefGoogle Scholar
  135. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, Tsujimoto Y (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6:1221–1228PubMedCrossRefGoogle Scholar
  136. Shimomura H, Terasaki F, Hayashi T, Kitaura Y, Isomura T, Suma H (2001) Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy. Jpn Circ J 65:965–968PubMedCrossRefGoogle Scholar
  137. Shintani T, Klionsky DJ (2004) Autophagy in health and disease: a double-edged sword. Science 306:990–995PubMedPubMedCentralCrossRefGoogle Scholar
  138. Shringarpure R, Grune T, Mehlhase J, Davies KJ (2003) Ubiquitin conjugation is not required for the degradation of oxidized proteins by proteasome. J Biol Chem 278:311–318PubMedCrossRefGoogle Scholar
  139. Stansfield WE, Moss NC, Willis MS, Tang R, Selzman CH (2007) Proteasome inhibition attenuates infarct size and preserves cardiac function in a murine model of myocardial ischemia-reperfusion injury. Ann Thorac Surg 84:120–125PubMedCrossRefGoogle Scholar
  140. Stansfield WE, Tang RH, Moss NC, Baldwin AS, Willis MS, Selzman CH (2008) Proteasome inhibition promotes regression of left ventricular hypertrophy. Am J Physiol Heart Circ Physiol 294:H645–H650PubMedCrossRefGoogle Scholar
  141. Steinberg SF (2013) Oxidative stress and sarcomeric proteins. Circ Res 112:393–405PubMedPubMedCentralCrossRefGoogle Scholar
  142. Strehl B, Seifert U, Kruger E, Heink S, Kuckelkorn U, Kloetzel PM (2005) Interferon-gamma, the functional plasticity of the ubiquitin-proteasome system, and MHC class I antigen processing. Immunol Rev 207:19–30PubMedCrossRefGoogle Scholar
  143. Sun M, Ouzounian M, de Couto G, Chen M, Yan R, Fukuoka M, Li G, Moon M, Liu Y, Gramolini A, Wells GJ, Liu PP (2013) Cathepsin-L ameliorates cardiac hypertrophy through activation of the autophagy-lysosomal dependent protein processing pathways. J Am Heart Assoc 2:e000191PubMedPubMedCentralCrossRefGoogle Scholar
  144. Szalay G, Meiners S, Voigt A, Lauber J, Spieth C, Speer N, Sauter M, Kuckelkorn U, Zell A, Klingel K, Stangl K, Kandolf R (2006) Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial immunoproteasomes. Am J Pathol 168:1542–1552PubMedPubMedCentralCrossRefGoogle Scholar
  145. Takagi H, Hsu CP, Kajimoto K, Shao D, Yang Y, Maejima Y, Zhai P, Yehia G, Yamada C, Zablocki D, Sadoshima J (2010) Activation of PKN mediates survival of cardiac myocytes in the heart during ischemia/reperfusion. Circ Res 107:642–649PubMedPubMedCentralCrossRefGoogle Scholar
  146. Tanaka K, Ii K, Ichihara A, Waxman L, Goldberg AL (1986) A high molecular weight protease in the cytosol of rat liver. I. Purification, enzymological properties, and tissue distribution. J Biol Chem 261:15197–15203PubMedGoogle Scholar
  147. Tanaka Y, Guhde G, Suter A, Eskelinen EL, Hartmann D, Lullmann-Rauch R, Janssen PM, Blanz J, von Figura K, Saftig P (2000) Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406:902–906PubMedCrossRefGoogle Scholar
  148. Thrower JS, Hoffman L, Rechsteiner M, Pickart CM (2000) Recognition of the polyubiquitin proteolytic signal. EMBO J 19:94–102PubMedPubMedCentralCrossRefGoogle Scholar
  149. Tian Z, Zheng H, Li J, Li Y, Su H, Wang X (2012) Genetically induced moderate inhibition of the proteasome in cardiomyocytes exacerbates myocardial ischemia-reperfusion injury in mice. Circ Res 111:532–542PubMedPubMedCentralCrossRefGoogle Scholar
  150. Tsukamoto O, Minamino T, Okada K, Shintani Y, Takashima S, Kato H, Liao Y, Okazaki H, Asai M, Hirata A, Fujita M, Asano Y, Yamazaki S, Asanuma H, Hori M, Kitakaze M (2006) Depression of proteasome activities during the progression of cardiac dysfunction in pressure-overloaded heart of mice. Biochem Biophys Res Commun 340:1125–1133PubMedCrossRefGoogle Scholar
  151. Unno M, Mizushima T, Morimoto Y, Tomisugi Y, Tanaka K, Yasuoka N, Tsukihara T (2002) The structure of the mammalian 20S proteasome at 2.75 A resolution. Structure (Camb) 10:609–618CrossRefGoogle Scholar
  152. Usui S, Maejima Y, Pain J, Hong C, Cho J, Park JY, Zablocki D, Tian B, Glass DJ, Sadoshima J (2011) Endogenous muscle atrophy F-box mediates pressure overload-induced cardiac hypertrophy through regulation of nuclear factor-kappaB. Circ Res 109:161–171PubMedPubMedCentralCrossRefGoogle Scholar
  153. Van Kaer L, Ashton-Rickardt PG, Eichelberger M, Gaczynska M, Nagashima K, Rock KL, Goldberg AL, Doherty PC, Tonegawa S (1994) Altered peptidase and viral-specific T cell response in LMP2 mutant mice. Immunity 1:533–541PubMedCrossRefGoogle Scholar
  154. Varshavsky A (1996) The N-end rule: functions, mysteries, uses. Proc Natl Acad Sci U S A 93:12142–12149PubMedPubMedCentralCrossRefGoogle Scholar
  155. Verma R, Aravind L, Oania R, McDonald WH, Yates JR 3rd, Koonin EV, Deshaies RJ (2002) Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298:611–615PubMedCrossRefGoogle Scholar
  156. Vignier N, Schlossarek S, Fraysse B, Mearini G, Kramer E, Pointu H, Mougenot N, Guiard J, Reimer R, Hohenberg H, Schwartz K, Vernet M, Eschenhagen T, Carrier L (2009) Nonsense-mediated mRNA decay and ubiquitin-proteasome system regulate cardiac myosin-binding protein C mutant levels in cardiomyopathic mice. Circ Res 105:239–248PubMedCrossRefGoogle Scholar
  157. Walczak M, Martens S (2013) Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation. Autophagy 9:424–425PubMedPubMedCentralCrossRefGoogle Scholar
  158. Weekes J, Morrison K, Mullen A, Wait R, Barton P, Dunn MJ (2003) Hyperubiquitination of proteins in dilated cardiomyopathy. Proteomics 3:208–216PubMedCrossRefGoogle Scholar
  159. Willis MS, Ike C, Li L, Wang DZ, Glass DJ, Patterson C (2007) Muscle ring finger 1, but not muscle ring finger 2, regulates cardiac hypertrophy in vivo. Circ Res 100:456–459PubMedPubMedCentralCrossRefGoogle Scholar
  160. Willis MS, Rojas M, Li L, Selzman CH, Tang RH, Stansfield WE, Rodriguez JE, Glass DJ, Patterson C (2009) Muscle ring finger 1 mediates cardiac atrophy in vivo. Am J Physiol Heart Circ Physiol 296:H997–H1006PubMedPubMedCentralCrossRefGoogle Scholar
  161. Wohlschlaeger J, Sixt SU, Stoeppler T, Schmitz KJ, Levkau B, Tsagakis K, Vahlhaus C, Schmid C, Peters J, Schmid KW, Milting H, Baba HA (2010) Ventricular unloading is associated with increased 20s proteasome protein expression in the myocardium. J Heart Lung Transplant 29:125–132PubMedCrossRefGoogle Scholar
  162. Yan L, Vatner DE, Kim SJ, Ge H, Masurekar M, Massover WH, Yang G, Matsui Y, Sadoshima J, Vatner SF (2005) Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci U S A 102:13807–13812PubMedPubMedCentralCrossRefGoogle Scholar
  163. Yang Z, Huang J, Geng J, Nair U, Klionsky DJ (2006) Atg22 recycles amino acids to link the degradative and recycling functions of autophagy. Mol Biol Cell 17:5094–5104PubMedPubMedCentralCrossRefGoogle Scholar
  164. Zaha VG, Young LH (2012) AMP-activated protein kinase regulation and biological actions in the heart. Circ Res 111:800–814PubMedPubMedCentralCrossRefGoogle Scholar
  165. Zhao J, Zhai B, Gygi SP, Goldberg AL (2015) mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proc Natl Acad Sci U S A 112:15790–15797PubMedCrossRefGoogle Scholar
  166. Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, Le V, Levine B, Rothermel BA, Hill JA (2007) Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 117:1782–1793PubMedPubMedCentralCrossRefGoogle Scholar
  167. Zong C, Gomes AV, Drews O, Li X, Young GW, Berhane B, Qiao X, French SW, Bardag-Gorce F, Ping P (2006) Regulation of murine cardiac 20S proteasomes: role of associating partners. Circ Res 99:372–380PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Cardiovascular Physiology, Institute of Physiology and PathophysiologyHeidelberg UniversityHeidelbergGermany

Personalised recommendations