The COP9 signalosome is required for autophagy, proteasome-mediated proteolysis, and cardiomyocyte survival in adult mice

Huabo Su, Jie Li, Hanna Osinska, Faqian Li, Jeffrey Robbins, Jinbao Liu, Ning Wei, Xuejun Wang

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 postmitotic organ of adult vertebrates has not been determined. We sought to study the physiological role of CSN8/CSN in adult mouse hearts. Methods and Results-Csn8 was conditionally ablated in the cardiomyocytes of adult mice (CSN8CKO) 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 CSN8CKO 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 autophagiclysosomal pathway, critical to the removal of oxidized proteins in the heart.

Original languageEnglish (US)
Pages (from-to)1049-1057
Number of pages9
JournalCirculation: Heart Failure
Volume6
Issue number5
DOIs
StatePublished - Sep 1 2013

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Autophagy
Proteasome Endopeptidase Complex
Cardiac Myocytes
Proteolysis
Cullin Proteins
Ubiquitinated Proteins
Proteins
Critical Pathways
Protein Subunits
Dilated Cardiomyopathy
COP9 signalosome complex
Vertebrates

Keywords

  • Autophagy
  • COP9 signalosome
  • Heart
  • NEDD8
  • Proteasome endopeptidase complex

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

The COP9 signalosome is required for autophagy, proteasome-mediated proteolysis, and cardiomyocyte survival in adult mice. / Su, Huabo; Li, Jie; Osinska, Hanna; Li, Faqian; Robbins, Jeffrey; Liu, Jinbao; Wei, Ning; Wang, Xuejun.

In: Circulation: Heart Failure, Vol. 6, No. 5, 01.09.2013, p. 1049-1057.

Research output: Contribution to journalArticle

Su, Huabo ; Li, Jie ; Osinska, Hanna ; Li, Faqian ; Robbins, Jeffrey ; Liu, Jinbao ; Wei, Ning ; Wang, Xuejun. / The COP9 signalosome is required for autophagy, proteasome-mediated proteolysis, and cardiomyocyte survival in adult mice. In: Circulation: Heart Failure. 2013 ; Vol. 6, No. 5. pp. 1049-1057.
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AU - Robbins, Jeffrey

AU - Liu, Jinbao

AU - Wei, Ning

AU - Wang, Xuejun

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AB - 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 postmitotic organ of adult vertebrates has not been determined. We sought to study the physiological role of CSN8/CSN in adult mouse hearts. Methods and Results-Csn8 was conditionally ablated in the cardiomyocytes of adult mice (CSN8CKO) 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 CSN8CKO 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 autophagiclysosomal pathway, critical to the removal of oxidized proteins in the heart.

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