title: COP9 signalosome regulates autophagosome maturation.
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.
  
  
  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.
authors: Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, 414 E Clark Street, Vermillion, SD 57069, USA..
authors: Huabo
authors: H
authors: Su
authors: Faqian
authors: F
authors: Li
authors: Mark J
authors: MJ
authors: Ranek
authors: Ning
authors: N
authors: Wei
authors: Xuejun
authors: X
authors: Wang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000075686:COP9 Signalosome Complex; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D007425:Intracellular Membranes / Q000473:pathology / Q000502:physiology; D008247:Lysosomes / Q000502:physiology; D008561:Membrane Fusion / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism*; D010588:Phagosomes / Q000502:physiology; D059748:Proteolysis; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D002352:Carrier Proteins; C481538:Cops8 protein, mouse; D046912:Multiprotein Complexes; D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D020691:rab GTP-Binding Proteins