COP9 Signalosome Controls the Degradation of Cytosolic Misfolded Proteins and Protects Against Cardiac Proteotoxicity

Huabo Su, Jie Li, Hanming Zhang, Wenxia Ma, Ning Wei, Jinbao Liu, Xuejun Wang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)956-966
Number of pages11
JournalCirculation Research
Volume117
Issue number11
DOIs
StatePublished - Nov 6 2015

Fingerprint

Cullin Proteins
Ligases
Ubiquitination
Proteins
Proteolysis
Ubiquitin
Restrictive Cardiomyopathy
Ubiquitinated Proteins
Crystallins
Premature Mortality
Missense Mutation
Proteasome Endopeptidase Complex
COP9 signalosome complex
Cardiac Myocytes
Knockout Mice
Heart Diseases

Keywords

  • COP9 signalosome
  • Cops8
  • autophagy
  • desmin-related cardiomyopathy
  • proteasome
  • ubiquitin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

COP9 Signalosome Controls the Degradation of Cytosolic Misfolded Proteins and Protects Against Cardiac Proteotoxicity. / Su, Huabo; Li, Jie; Zhang, Hanming; Ma, Wenxia; Wei, Ning; Liu, Jinbao; Wang, Xuejun.

In: Circulation Research, Vol. 117, No. 11, 06.11.2015, p. 956-966.

Research output: Contribution to journalArticle

Su, Huabo ; Li, Jie ; Zhang, Hanming ; Ma, Wenxia ; Wei, Ning ; Liu, Jinbao ; Wang, Xuejun. / COP9 Signalosome Controls the Degradation of Cytosolic Misfolded Proteins and Protects Against Cardiac Proteotoxicity. In: Circulation Research. 2015 ; Vol. 117, No. 11. pp. 956-966.
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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

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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