COP9 signalosome regulates autophagosome maturation

Huabo Su, Faqian Li, Mark J. Ranek, Ning Wei, Xuejun Wang

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Background-: Autophagy is essential to intracellular homeostasis and is involved in the pathophysiology of a variety of diseases. Mechanisms regulating selective autophagy remain poorly understood. The COP9 signalosome (CSN) is a conserved protein complex consisting of 8 subunits (CSN1 through CSN8), and is known to regulate the ubiquitin-proteasome system. However, it is unknown whether CSN plays a role in autophagy. Methods and Results-: Marked increases in the LC3-II and p62 proteins were observed on Csn8 depletion in the cardiomyocytes of mouse hearts with cardiomyocyte-restricted knockout of the gene encoding CSN subunit 8 (CR-Csn8KO). The increases in autophagosomes were confirmed by probing with green fluorescent protein-LC3 and electron microscopy. Autophagic flux assessments revealed that defective autophagosome removal was the cause of autophagosome accumulation and occurred before a global ubiquitin-proteasome system impairment in Csn8-deficient hearts. Analyzing the prevalence of different stages of autophagic vacuoles revealed defective autophagosome maturation. Downregulation of Rab7 was found to colocalize strikingly with the autophagosome accumulation at the individual cardiomyocyte level. A significantly higher percent of cardiomyocytes with autophagosome accumulation underwent necrosis in CR-Csn8KO hearts. Long-term lysosomal inhibition with chloroquine induced cardiomyocyte necrosis in mice. Rab7 knockdown impaired autophagosome maturation of nonselective and selective autophagy and exacerbated cell death induced by proteasome inhibition in cultured cardiomyocytes. Conclusions-: Csn8/CSN is a central regulator in not only the proteasomal proteolytic pathway, but also selective autophagy. Likely through regulating the expression of Rab7, Csn8/CSN plays a critical role in autophagosome maturation. Impaired autophagosome maturation causes cardiomyocytes to undergo necrosis.

Original languageEnglish (US)
Pages (from-to)2117-2128
Number of pages12
JournalCirculation
Volume124
Issue number19
DOIs
StatePublished - Nov 8 2011
Externally publishedYes

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Cardiac Myocytes
Autophagy
Proteasome Endopeptidase Complex
Necrosis
Ubiquitin
Autophagosomes
COP9 signalosome complex
Gene Knockout Techniques
Chloroquine
Vacuoles
Green Fluorescent Proteins
Electron Microscopy
Proteins
Homeostasis
Cell Death
Down-Regulation

Keywords

  • COP9 signalosome complex
  • autophagy
  • lysosomes
  • necrosis
  • rab7 protein

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

COP9 signalosome regulates autophagosome maturation. / Su, Huabo; Li, Faqian; Ranek, Mark J.; Wei, Ning; Wang, Xuejun.

In: Circulation, Vol. 124, No. 19, 08.11.2011, p. 2117-2128.

Research output: Contribution to journalArticle

Su, H, Li, F, Ranek, MJ, Wei, N & Wang, X 2011, 'COP9 signalosome regulates autophagosome maturation', Circulation, vol. 124, no. 19, pp. 2117-2128. https://doi.org/10.1161/CIRCULATIONAHA.111.048934
Su, Huabo ; Li, Faqian ; Ranek, Mark J. ; Wei, Ning ; Wang, Xuejun. / COP9 signalosome regulates autophagosome maturation. In: Circulation. 2011 ; Vol. 124, No. 19. pp. 2117-2128.
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