PMID- 21986281
OWN - NLM
STAT- MEDLINE
DCOM- 20120105
LR  - 20240308
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Print)
IS  - 0009-7322 (Linking)
VI  - 124
IP  - 19
DP  - 2011 Nov 8
TI  - COP9 signalosome regulates autophagosome maturation.
PG  - 2117-28
LID - 10.1161/CIRCULATIONAHA.111.048934 [doi]
AB  - 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.
FAU - Su, Huabo
AU  - Su H
AD  - Division of Basic Biomedical Sciences, Sanford School of Medicine of the 
      University of South Dakota, 414 E Clark Street, Vermillion, SD 57069, USA..
FAU - Li, Faqian
AU  - Li F
FAU - Ranek, Mark J
AU  - Ranek MJ
FAU - Wei, Ning
AU  - Wei N
FAU - Wang, Xuejun
AU  - Wang X
LA  - eng
GR  - R01 HL085629-02/HL/NHLBI NIH HHS/United States
GR  - R01 HL072166-06A1S1/HL/NHLBI NIH HHS/United States
GR  - R01 HL072166-09/HL/NHLBI NIH HHS/United States
GR  - R01HL072166/HL/NHLBI NIH HHS/United States
GR  - R01 HL085629-03/HL/NHLBI NIH HHS/United States
GR  - R01 HL085629-05/HL/NHLBI NIH HHS/United States
GR  - R01 HL072166-06A1/HL/NHLBI NIH HHS/United States
GR  - R01HL085629/HL/NHLBI NIH HHS/United States
GR  - P20 RR015567/RR/NCRR NIH HHS/United States
GR  - 5P20RR015567/RR/NCRR NIH HHS/United States
GR  - R01 HL085629-04/HL/NHLBI NIH HHS/United States
GR  - R01 HL072166-07/HL/NHLBI NIH HHS/United States
GR  - R01 HL072166/HL/NHLBI NIH HHS/United States
GR  - R01 HL072166-08/HL/NHLBI NIH HHS/United States
GR  - R01 HL085629/HL/NHLBI NIH HHS/United States
GR  - R01 HL085629-01/HL/NHLBI NIH HHS/United States
GR  - R01 HL085629-04W1/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111010
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Carrier Proteins)
RN  - 0 (Cops8 protein, mouse)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (rab7 GTP-Binding Proteins)
RN  - 0 (rab7 GTP-binding proteins, mouse)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - EC 3.4.19.12 (COP9 Signalosome Complex)
RN  - EC 3.6.5.2 (rab GTP-Binding Proteins)
SB  - IM
MH  - Animals
MH  - Autophagy/*physiology
MH  - COP9 Signalosome Complex
MH  - Carrier Proteins/*genetics/*metabolism
MH  - Cells, Cultured
MH  - Down-Regulation/physiology
MH  - Intracellular Membranes/pathology/physiology
MH  - Lysosomes/physiology
MH  - Membrane Fusion/physiology
MH  - Mice
MH  - Mice, Transgenic
MH  - Multiprotein Complexes/*genetics/*metabolism
MH  - Myocytes, Cardiac/*metabolism/pathology
MH  - Necrosis/metabolism/pathology
MH  - Peptide Hydrolases/*genetics/*metabolism
MH  - Phagosomes/physiology
MH  - Proteolysis
MH  - rab GTP-Binding Proteins/metabolism
MH  - rab7 GTP-Binding Proteins
PMC - PMC3211066
MID - NIHMS331861
COIS- Conflict of Interest Disclosures: None.
EDAT- 2011/10/12 06:00
MHDA- 2012/01/06 06:00
PMCR- 2012/11/08
CRDT- 2011/10/12 06:00
PHST- 2011/10/12 06:00 [entrez]
PHST- 2011/10/12 06:00 [pubmed]
PHST- 2012/01/06 06:00 [medline]
PHST- 2012/11/08 00:00 [pmc-release]
AID - CIRCULATIONAHA.111.048934 [pii]
AID - 10.1161/CIRCULATIONAHA.111.048934 [doi]
PST - ppublish
SO  - Circulation. 2011 Nov 8;124(19):2117-28. doi: 10.1161/CIRCULATIONAHA.111.048934. 
      Epub 2011 Oct 10.