title: COP9 signalosome controls the degradation of cytosolic misfolded proteins and protects against cardiac proteotoxicity.
abstract: BACKGROUND
  Impaired degradation of misfolded proteins is associated with a large subset of heart diseases. Misfolded proteins are degraded primarily by the ubiquitin-proteasome system, but the ubiquitin ligases responsible for the degradation remain largely unidentified. The cullin deneddylation activity of the COP9 signalosome (CSN) requires all 8 CSN subunits (CSN1 through CSN8) and regulates cullin-RING ligases, thereby controlling ubiquitination of a large number of proteins; however, neither CSN nor cullin-RING ligases is known to regulate the degradation of cytosolic misfolded proteins.
  
  
  OBJECTIVE
  We sought to investigate the role of CSN8/CSN in misfolded protein degradation and cardiac proteinopathy.
  
  
  RESULTS
  Cardiac CSN8 knockout causes mouse premature death; hence, CSN8 hypomorphism (CSN8(hypo)) mice were used. Myocardial neddylated forms of cullins were markedly increased, and myocardial capacity of degrading a surrogate misfolded protein was significantly reduced by CSN8 hypomorphism. When introduced into proteinopathic mice in which a bona fide misfolded protein R120G missense mutation of αβ-crystallin (CryAB(R120G)) is overexpressed in the heart, CSN8 hypomorphism aggravated CryAB(R120G)-induced restrictive cardiomyopathy and shortened the lifespan of CryAB(R120G) mice, which was associated with augmented accumulation of protein aggregates, increased neddylated proteins, and reduced levels of total ubiquitinated proteins and LC3-II in the heart. In cultured cardiomyocytes, both CSN8 knockdown and cullin-RING ligase inactivation suppressed the ubiquitination and degradation of CryAB(R120G) but not native CryAB, resulting in accumulation of protein aggregates and exacerbation of CryAB(R120G) cytotoxicity.
  
  
  CONCLUSIONS
  (1) CSN8/CSN promotes the ubiquitination and degradation of misfolded proteins and protects against cardiac proteotoxicity, and (2) cullin-RING ligases participate in degradation of cytosolic misfolded proteins.
authors.affiliation: From the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.).
authors.forename: Huabo
authors.initials: H
authors.lastname: Su
authors.affiliation: From the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.).
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.).
authors.forename: Hanming
authors.initials: H
authors.lastname: Zhang
authors.affiliation: From the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.).
authors.forename: Wenxia
authors.initials: W
authors.lastname: Ma
authors.affiliation: From the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.).
authors.forename: Ning
authors.initials: N
authors.lastname: Wei
authors.affiliation: From the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.). xuejun.wang@usd.edu jliu@gzhmu.edu.cn.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Respiratory Disease and Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China (H.S., J.Liu, X.W.); Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion (H.S., J.Li, H.Z., J.Liu, X.W.); Vascular Biology Center (H.S., J.Li, W.M.) and Department of Pharmacology and Toxicology (H.S.), Medical College of Georgia, Georgia Regents University, Augusta; and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT (N.W.). xuejun.wang@usd.edu jliu@gzhmu.edu.cn.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D000075686:COP9 Signalosome Complex; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017510:Protein Folding; D059748:Proteolysis; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination; D038203:alpha-Crystallin B Chain / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C481538:Cops8 protein, mouse; C525420:Cryab protein, mouse; D044842:Cullin Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D038203:alpha-Crystallin B Chain; D000075686:COP9 Signalosome Complex
keywords: COP9 signalosome; Cops8; autophagy; desmin-related cardiomyopathy; proteasome; ubiquitin