title: The COP9 signalosome is required for autophagy, proteasome-mediated proteolysis, and cardiomyocyte survival in adult mice.
abstract: BACKGROUND
  The COP9 signalosome (CSN) is an evolutionarily conserved protein complex composed of 8 unique protein subunits (CSN1 through CSN8). We have recently discovered in perinatal mouse hearts that CSN regulates not only proteasome-mediated proteolysis but also macroautophagy. However, the physiological significance of CSN in a post-mitotic organ of adult vertebrates has not been determined. We sought to study the physiological role of CSN8/CSN in adult mouse hearts.
  
  
  RESULTS
  Csn8 was conditionally ablated in the cardiomyocytes of adult mice (CSN8(CKO)) using a temporally controlled Cre-LoxP system. Loss of CSN8 accumulated the neddylated forms of cullins and noncullin proteins, increased ubiquitinated proteins, and stabilized a surrogate substrate of the proteasome in the heart. Autophagic flux was significantly decreased, whereas autophagosomes were markedly increased in CSN8(CKO) hearts, indicative of impaired autophagosome removal. Furthermore, we observed increased oxidized proteins, massive necrotic cardiomyocytes, and morphological and functional changes characteristic of dilated cardiomyopathy in CSN8(CKO) mice.
  
  
  CONCLUSIONS
  CSN deneddylates substrates more than cullins and is indispensable to cardiomyocyte survival in not only perinatal hearts but also adult hearts. CSN8/CSN regulates both proteasome-mediated proteolysis and the autophagic-lysosomal pathway, critical to the removal of oxidized proteins in the heart.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD.
authors.forename: Huabo
authors.initials: H
authors.lastname: Su
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: Faqian
authors.initials: F
authors.lastname: Li
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Wei
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy; D000075686:COP9 Signalosome Complex; D002311:Cardiomyopathy, Dilated / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D044842:Cullin Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D000075687:NEDD8 Protein; D009336:Necrosis; D010084:Oxidation-Reduction; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C481538:Cops8 protein, mouse; D044842:Cullin Proteins; D046912:Multiprotein Complexes; D000075687:NEDD8 Protein; C513172:Nedd8 protein, mouse; D014452:Ubiquitins; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D046988:Proteasome Endopeptidase Complex
keywords: COP9 signalosome; NEDD8; autophagy; heart; proteasome endopeptidase complex