Abstract P043: The COP9 Signalosome Regulates Autophagy
By indiscriminately degrading portions of cytoplasm for self-supply of nutrients, non-selective autophagy helps the cell to survive starvation. Selective autophagy, however, removes defective/surplus organelles and protein aggregates, thereby playing an important role in quality control in the cell. Autophagy is involved in the pathophysiology of a variety of disease, including common forms of heart disease. Mechanisms regulating autophagy, especially selective autophagy, remain poorly understood. The COP9 signalosome (CSN) is an evolutionarily conserved protein complex consisting of 8 subunits (CSN1 through CSN8). CSN was purported to regulate ubiquitin-proteasome system (UPS) mediated proteolysis. We recently reported UPS malfunction and the accumulation of ubiquitin positive aggregates in the cardiomyocytes of mice with perinatal cardiomyocyte-restricted Csn8 knockout (CR-Csn8KO), which displayed massive cardiomyocyte necrosis, congestive heart failure, and premature death. Here we report that Csn8/CSN is required for the removal of autophagosomes in cardiomyocytes, an exciting discovery that has not been reported in any types of cells. CR-Csn8KO mouse hearts show marked increases in LC3-II, indicative of increased autophagosomes. The increase in LC-II is accompanied by a significant increase in p62 protein levels, which is evident as early as 1 week of age, long before the accumulation of a surrogate UPS substrate becomes discernible. The increase in autophagosomes is confirmed by probing with a transgenic GFP-LC3 and by electron microscopy. Autophagic flux assessments reveal that the removal of autophagosomes in cardiomyocytes is impaired by Csn8 deficiency and the defective fusion between autophagosomes and lysosomes may be responsible. Rab7 transcript and protein levels in the heart are significantly decreased by Csn8 deficiency. Confocal microscopy reveals a striking reciprocal relationship between increases in GFP-LC3 puncta and the decreased Rab7 expression. Rab7 knockdown impairs the removal of autophagosomes in cultured cardiomyocytes. Hence, Csn8/CSN is a central regulator in not only the UPS but also autophagy. Csn8/CSN supports autophagosome-lysosome fusion likely by stimulating Rab7 expression.
- © 2011 by American Heart Association, Inc.