title: Proteasome malfunction activates macroautophagy in the heart.
abstract: Protein quality control (PQC) senses and repairs misfolded/unfolded proteins and, if the repair fails, degrades the terminally misfolded polypeptides through an intricate collaboration between molecular chaperones and targeted proteolysis. Proteolysis of damaged proteins is performed primarily by the ubiquitin-proteasome system (UPS). Macroautophagy (commonly known as autophagy) may also play a role in PQC-associated proteolysis, especially when UPS function becomes inadequate. The development of a range of heart diseases, including bona fide cardiac proteinopathies and various forms of cardiac dysfunction has been linked to proteasome functional insufficiency (PFI). Both PFI and activation of autophagy have been observed in the heart of well-established mouse models of cardiac proteinopathy. A causal relationship between PFI and autophagic activation was suggested by a study using cultured cardiomyocytes but has not been established in the heart of intact animals. Taking advantage of an autophagy reporter, we demonstrated here that pharmacologically induced proteasome inhibition is sufficient to activate autophagy in cardiomyocytes in both intact animals and cell cultures, unveiling a potential cross-talk between the two major degradation pathways in cardiac PQC.
authors.affiliation: Protein Quality Control and Degradation Research Center, Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota Vermillion, SD 57069, USA.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Zheng
authors.forename: Huabo
authors.initials: H
authors.lastname: Su
authors.forename: Zongwen
authors.initials: Z
authors.lastname: Tian
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
references.citation: Cell. 2007 Dec 14;131(6):1149-63
references.pmid: 18083104
references.citation: Hum Mol Genet. 2005 Oct 1;14(19):2787-99
references.pmid: 16103128
references.citation: Nature. 2008 Aug 28;454(7208):1088-95
references.pmid: 18756251
references.citation: Circ Res. 2005 Nov 11;97(10):1018-26
references.pmid: 16210548
references.citation: Cell. 2009 Jun 12;137(6):1062-75
references.pmid: 19524509
references.citation: Cell Death Differ. 2007 Feb;14(2):230-9
references.pmid: 16794605
references.citation: Mol Cell Biol. 2006 Dec;26(24):9220-31
references.pmid: 17030611
references.citation: J Biol Chem. 2005 Dec 2;280(48):40282-92
references.pmid: 16192271
references.citation: J Biol Chem. 2007 Feb 16;282(7):4702-4710
references.pmid: 17135238
references.citation: Nat Med. 2007 May;13(5):619-24
references.pmid: 17450150
references.citation: Biochem J. 2003 Oct 1;375(Pt 1):75-86
references.pmid: 12841850
references.citation: Ann Neurol. 2002 Oct;52(4):498-503
references.pmid: 12325080
references.citation: FASEB J. 2006 Feb;20(2):362-4
references.pmid: 16371426
references.citation: J Mol Cell Cardiol. 2006 Apr;40(4):451-4
references.pmid: 16481005
references.citation: Mol Cell Biol. 2004 Aug;24(16):7130-9
references.pmid: 15282312
references.citation: Mol Cell Biol. 2004 Dec;24(24):10941-53
references.pmid: 15572695
references.citation: Mol Cell. 2009 Feb 27;33(4):517-27
references.pmid: 19250912
references.citation: FASEB J. 2005 Dec;19(14):2051-3
references.pmid: 16188962
references.citation: Circ Res. 2006 Dec 8;99(12):1315-28
references.pmid: 17158347
references.citation: Nat Cell Biol. 2010 Mar;12(3):213-23
references.pmid: 20173742
references.citation: Circulation. 2008 Jun 17;117(24):3070-8
references.pmid: 18541737
references.citation: Cardiovasc Res. 2010 Dec 1;88(3):424-33
references.pmid: 20601385
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15671-6
references.pmid: 9861028
references.citation: Autophagy. 2008 Feb;4(2):141-50
references.pmid: 17986870
references.citation: Cell. 2009 Jun 12;137(6):1001-4
references.pmid: 19524504
references.citation: Circ Res. 2011 Jul 22;109(3):296-308
references.pmid: 21659648
references.citation: Annu Rev Biochem. 2005;74:739-89
references.pmid: 15952902
references.citation: Biochem Biophys Res Commun. 2004 Jan 9;313(2):453-8
references.pmid: 14684184
references.citation: Trends Cell Biol. 1998 Oct;8(10):397-403
references.pmid: 9789328
references.citation: Nature. 2006 Jun 15;441(7095):880-4
references.pmid: 16625205
references.citation: Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1677-91
references.pmid: 16987021
references.citation: Clin Chem. 2000 May;46(5):673-83
references.pmid: 10794750
references.citation: Autophagy. 2008 Feb;4(2):151-75
references.pmid: 18188003
references.citation: J Clin Invest. 2010 Jan;120(1):127-41
references.pmid: 20038797
references.citation: Nature. 2006 Jun 15;441(7095):885-9
references.pmid: 16625204
references.citation: Int J Biochem Cell Biol. 2004 Dec;36(12):2551-62
references.pmid: 15325592
references.citation: PLoS One. 2008;3(10):e3391
references.pmid: 18852889
references.citation: J Biol Chem. 2007 Aug 17;282(33):24131-45
references.pmid: 17580304
references.citation: Cell. 2006 Nov 3;127(3):591-606
references.pmid: 17081980
references.citation: Curr Opin Cell Biol. 1995 Apr;7(2):215-23
references.pmid: 7612274
references.citation: J Cell Biol. 2005 Nov 21;171(4):603-14
references.pmid: 16286508
references.citation: Bioorg Med Chem Lett. 1998 Feb 17;8(4):333-8
references.pmid: 9871680
references.citation: Panminerva Med. 2010 Mar;52(1):9-25
references.pmid: 20228723
references.citation: Autophagy. 2005 Apr;1(1):11-22
references.pmid: 16874045
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12923-8
references.pmid: 16905651
references.citation: Hum Mol Genet. 2008 Feb 1;17(3):431-9
references.pmid: 17981811
references.citation: Mol Biol Cell. 2004 Mar;15(3):1101-11
references.pmid: 14699058
references.citation: Cardiovasc Res. 2010 Jan 15;85(2):253-62
references.pmid: 19696071
references.citation: J Biol Chem. 2010 Jul 16;285(29):22576-91
references.pmid: 20452972
references.citation: Nat Cell Biol. 2007 Oct;9(10):1102-9
references.pmid: 17909521
references.citation: Biochim Biophys Acta. 2011 Feb;1809(2):141-9
references.pmid: 20840877
references.citation: Mol Cell Biol. 2004 Sep;24(18):8055-68
references.pmid: 15340068
references.citation: Mol Cell. 2009 May 15;34(3):259-69
references.pmid: 19450525
references.citation: J Mol Cell Cardiol. 2007 Jan;42(1):265-9
references.pmid: 17140599
references.citation: Mol Cell Biol. 2004 Oct;24(19):8477-86
references.pmid: 15367669
references.citation: Hum Mol Genet. 2007 Mar 15;16(6):618-29
references.pmid: 17331981
references.citation: Biochem Biophys Res Commun. 2001 Jan 12;280(1):223-8
references.pmid: 11162503
references.citation: Physiol Rev. 2007 Oct;87(4):1377-408
references.pmid: 17928587
references.citation: J Biol Chem. 2006 Oct 6;281(40):29776-87
references.pmid: 16882669
references.citation: Int J Biochem Cell Biol. 2003 May;35(5):651-64
references.pmid: 12672457