COP9 Signalosome Regulates Autophagosome Maturation

• DOI: 10.1161/circulationaha.111.048934
• Publication Date: 2011-10-11T05:29:30Z
• Authors: Huabo Su; Faqian Li; Mark J. Ranek; Ning Wei; Xuejun Wang
• Keywords: Autophagosome; COP9 signalosome

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