title: The interplay between autophagy and the ubiquitin-proteasome system in cardiac proteotoxicity.
abstract: Proteotoxicity refers to the detrimental effects of damaged/misfolded proteins on the cell. Cardiac muscle is particularly susceptible to proteotoxicity because sustained and severe proteotoxic stress leads to cell death and the cardiac muscle has very limited self-renewal capacity. The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) are two major pathways responsible for degradation of most cellular proteins. Alterations of UPS and ALP functions are associated with the accumulation of proteotoxic species in the heart, a key pathological feature of common forms of heart disease including idiopathic, ischemic, and pressure-overloaded cardiomyopathies and a large subset of congestive heart failure. Emerging evidence suggests that proteasome inhibition or impairment activates autophagy and conversely, acute ALP inhibition may sometimes increase intrinsic proteasome peptidase activities but chronic ALP inhibition hinders UPS performance in ubiquitinated protein degradation. The exact molecular basis on which the two degradative pathways interact remains largely undefined. Here we review current understanding of the roles of the UPS and autophagy in the control of cardiac proteotoxicity, with a specific focus on the crosstalk between the two pathways. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Changhua
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA. Electronic address: Xuejun.Wang@usd.edu.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000633:toxicity*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D011506:Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: Autophagy; Heart disease; Proteotoxicity; Ubiquitin–proteasome system
references.citation: Arch Biochem Biophys. 2006 Sep 1;453(1):135-42
references.pmid: 16530722
references.citation: Cancer Res. 2009 May 15;69(10):4415-23
references.pmid: 19417138
references.citation: Mol Oncol. 2013 Dec;7(6):1012-8
references.pmid: 23916134
references.citation: Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1220-8
references.pmid: 21784990
references.citation: Circ Res. 2010 Nov 12;107(10):1185-97
references.pmid: 21071716
references.citation: Circulation. 2006 Oct 24;114(17):1821-8
references.pmid: 17043166
references.citation: Circulation. 2012 Jun 26;125(25):3170-81
references.pmid: 22592897
references.citation: Biochemistry. 2005 Oct 25;44(42):13893-901
references.pmid: 16229478
references.citation: Oncogene. 2010 Jan 21;29(3):451-62
references.pmid: 19881538
references.citation: J Clin Invest. 2011 Sep;121(9):3689-700
references.pmid: 21841311
references.citation: Trends Cell Biol. 2012 Aug;22(8):407-17
references.pmid: 22748206
references.citation: Am J Neurodegener Dis. 2013;2(1):1-14
references.pmid: 23516262
references.citation: FASEB J. 2006 Feb;20(2):362-4
references.pmid: 16371426
references.citation: Circ Heart Fail. 2013 Sep 1;6(5):1049-57
references.pmid: 23873473
references.citation: J Mol Cell Cardiol. 2006 Apr;40(4):451-4
references.pmid: 16481005
references.citation: Sci Signal. 2013 Oct 01;6(295):ra86
references.pmid: 24084648
references.citation: Mol Cell. 2009 Feb 27;33(4):517-27
references.pmid: 19250912
references.citation: J Mol Cell Cardiol. 1999 Feb;31(2):467-76
references.pmid: 10093058
references.citation: J Biol Chem. 2006 Oct 6;281(40):30299-304
references.pmid: 16901900
references.citation: Circ Res. 2011 Jan 7;108(1):40-50
references.pmid: 21051661
references.citation: Mol Biol Cell. 2004 Nov;15(11):4829-40
references.pmid: 15331765
references.citation: Circ Res. 2007 Mar 30;100(6):914-22
references.pmid: 17332429
references.citation: Autophagy. 2013 Oct;9(10):1500-8
references.pmid: 23934082
references.citation: Mol Brain. 2008 Nov 21;1:17
references.pmid: 19021916
references.citation: Cell. 2010 Nov 24;143(5):682-5
references.pmid: 21111229
references.citation: Circ Res. 2006 Dec 8;99(12):1315-28
references.pmid: 17158347
references.citation: J Biol Chem. 2001 Aug 10;276(32):30057-63
references.pmid: 11375979
references.citation: Autophagy. 2008 Feb;4(2):195-204
references.pmid: 18059169
references.citation: FASEB J. 2005 Dec;19(14):2051-3
references.pmid: 16188962
references.citation: Mol Biol Cell. 2008 May;19(5):2179-92
references.pmid: 18337468
references.citation: N Engl J Med. 2013 Jan 31;368(5):455-64
references.pmid: 23363499
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10132-6
references.pmid: 15220483
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4377-82
references.pmid: 17360532
references.citation: Circulation. 2008 Jun 17;117(24):3070-8
references.pmid: 18541737
references.citation: Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2836-42
references.pmid: 15665051
references.citation: Cardiovasc Res. 2010 Dec 1;88(3):424-33
references.pmid: 20601385
references.citation: Autophagy. 2013 Oct;9(10):1455-66
references.pmid: 23959233
references.citation: Nature. 2007 Jun 14;447(7146):859-63
references.pmid: 17568747
references.citation: Am J Cardiovasc Dis. 2011;1(3):214-26
references.pmid: 22081794
references.citation: Circ Res. 2011 Jul 22;109(3):296-308
references.pmid: 21659648
references.citation: Int J Cardiol. 2013 Oct 12;168(5):4667-77
references.pmid: 23938216
references.citation: Nat Biotechnol. 2003 Aug;21(8):897-902
references.pmid: 12872133
references.citation: Autophagy. 2012 Mar;8(3):297-309
references.pmid: 22302006
references.citation: Cell Death Dis. 2013 Nov 21;4:e925
references.pmid: 24263099
references.citation: Mol Cell Biol. 2014 Apr;34(7):1336-48
references.pmid: 24469403
references.citation: Am J Physiol Heart Circ Physiol. 2013 May 15;304(10):H1283-93
references.pmid: 23479263
references.citation: Circulation. 2008 May 27;117(21):2743-51
references.pmid: 18490523
references.citation: J Clin Invest. 2013 Dec;123(12):5284-97
references.pmid: 24177425
references.citation: J Mol Cell Cardiol. 2008 Jul;45(1):11-27
references.pmid: 18495153
references.citation: Cell Cycle. 2012 Jun 1;11(11):2092-9
references.pmid: 22580468
references.citation: Science. 2001 May 25;292(5521):1552-5
references.pmid: 11375494
references.citation: J Mol Cell Cardiol. 2014 Jun;71:3-10
references.pmid: 24380730
references.citation: Biochim Biophys Acta. 2008 Dec;1782(12):691-9
references.pmid: 18930136
references.citation: Circulation. 2013 Jul 23;128(4):365-76
references.pmid: 23770744
references.citation: Circ Res. 2011 Jul 8;109(2):151-60
references.pmid: 21617129
references.citation: Cell. 1994 Sep 9;78(5):761-71
references.pmid: 8087844
references.citation: Circ Res. 2001 Jul 6;89(1):84-91
references.pmid: 11440982
references.citation: Circ Res. 2005 Nov 11;97(10):1018-26
references.pmid: 16210548
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13807-12
references.pmid: 16174725
references.citation: J Mol Cell Biol. 2013 Aug;5(4):214-26
references.pmid: 23918283
references.citation: Trends Cell Biol. 2000 Dec;10(12):524-30
references.pmid: 11121744
references.citation: Eur J Biochem. 1995 Feb 1;227(3):792-800
references.pmid: 7867640
references.citation: J Mol Cell Cardiol. 2014 Jun;71:16-24
references.pmid: 24239609
references.citation: Cell Metab. 2013 Sep 3;18(3):380-91
references.pmid: 24011073
references.citation: Am J Physiol Heart Circ Physiol. 2013 Aug 15;305(4):H551-62
references.pmid: 23729213
references.citation: Panminerva Med. 2010 Mar;52(1):9-25
references.pmid: 20228723
references.citation: J Am Heart Assoc. 2013 Apr 22;2(2):e000191
references.pmid: 23608608
references.citation: Autophagy. 2006 Oct-Dec;2(4):305-6
references.pmid: 16874046
references.citation: Prog Mol Biol Transl Sci. 2012;109:295-346
references.pmid: 22727426
references.citation: Circulation. 2014 Mar 11;129(10):1139-51
references.pmid: 24396039
references.citation: Genes Dev. 2013 Jun 15;27(12):1365-77
references.pmid: 23788623
references.citation: Toxicol Lett. 2014 Mar 21;225(3):333-41
references.pmid: 24440343
references.citation: Free Radic Biol Med. 2006 Jan 1;40(1):156-64
references.pmid: 16337889
references.citation: J Mol Cell Cardiol. 2013 Feb;55:73-84
references.pmid: 23046644
references.citation: J Mol Med (Berl). 2003 Apr;81(4):235-45
references.pmid: 12700891
references.citation: Pathobiology. 2014;81(1):8-14
references.pmid: 23969338
references.citation: Cell Death Differ. 2007 Feb;14(2):230-9
references.pmid: 16794605
references.citation: Autophagy. 2011 Nov;7(11):1382-3
references.pmid: 21997373
references.citation: Mol Cell Biol. 2006 Dec;26(24):9220-31
references.pmid: 17030611
references.citation: J Exp Med. 1998 Jan 5;187(1):97-104
references.pmid: 9419215
references.citation: Autophagy. 2012 Sep;8(9):1394-6
references.pmid: 22889942
references.citation: Am J Physiol Heart Circ Physiol. 2013 Feb 1;304(3):H337-49
references.pmid: 23220331
references.citation: Circulation. 2011 Nov 8;124(19):2117-28
references.pmid: 21986281
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9745-50
references.pmid: 18621691
references.citation: J Biol Chem. 2006 Oct 6;281(40):29776-87
references.pmid: 16882669
references.citation: Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H919-26
references.pmid: 12424098
references.citation: EMBO J. 2010 Mar 3;29(5):969-80
references.pmid: 20075865
references.citation: Circ Res. 2013 Jan 18;112(2):367-81
references.pmid: 23329792
references.citation: PLoS One. 2014 Jun 24;9(6):e100715
references.pmid: 24959866
references.citation: Mol Cell. 2010 Oct 22;40(2):238-52
references.pmid: 20965419
references.citation: Circulation. 2001 May 15;103(19):2402-7
references.pmid: 11352891
references.citation: FASEB J. 2011 Mar;25(3):883-93
references.pmid: 21098724
references.citation: Circ Res. 2012 Aug 17;111(5):532-42
references.pmid: 22740087