TY - JOUR
T1 - COP9 Signalosome Controls the Degradation of Cytosolic Misfolded Proteins and Protects Against Cardiac Proteotoxicity
AU - Su, Huabo
AU - Li, Jie
AU - Zhang, Hanming
AU - Ma, Wenxia
AU - Wei, Ning
AU - Liu, Jinbao
AU - Wang, Xuejun
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/11/6
Y1 - 2015/11/6
N2 - Rationale: 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. Methods and Results: Cardiac CSN8 knockout causes mouse premature death; hence, CSN8 hypomorphism (CSN8hypo) 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 (CryABR120G) is overexpressed in the heart, CSN8 hypomorphism aggravated CryABR120G-induced restrictive cardiomyopathy and shortened the lifespan of CryABR120G 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 CryABR120G but not native CryAB, resulting in accumulation of protein aggregates and exacerbation of CryABR120G 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.
AB - Rationale: 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. Methods and Results: Cardiac CSN8 knockout causes mouse premature death; hence, CSN8 hypomorphism (CSN8hypo) 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 (CryABR120G) is overexpressed in the heart, CSN8 hypomorphism aggravated CryABR120G-induced restrictive cardiomyopathy and shortened the lifespan of CryABR120G 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 CryABR120G but not native CryAB, resulting in accumulation of protein aggregates and exacerbation of CryABR120G 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.
KW - COP9 signalosome
KW - Cops8
KW - autophagy
KW - desmin-related cardiomyopathy
KW - proteasome
KW - ubiquitin
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UR - http://www.scopus.com/inward/citedby.url?scp=84946496048&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.115.306783
DO - 10.1161/CIRCRESAHA.115.306783
M3 - Article
C2 - 26383969
AN - SCOPUS:84946496048
SN - 0009-7330
VL - 117
SP - 956
EP - 966
JO - Circulation research
JF - Circulation research
IS - 11
ER -