BACKGROUND: The COP9 signalosome (CSN) is an evolutionarily conserved protein complex composed of 8 unique protein subunits (CSN1 through CSN8). We have recently discovered in perinatal mouse hearts that CSN regulates not only proteasome-mediated proteolysis but also macroautophagy. However, the physiological significance of CSN in a post-mitotic organ of adult vertebrates has not been determined. We sought to study the physiological role of CSN8/CSN in adult mouse hearts. METHODS AND RESULTS: Csn8 was conditionally ablated in the cardiomyocytes of adult mice (CSN8(CKO)) using a temporally controlled Cre-LoxP system. Loss of CSN8 accumulated the neddylated forms of cullins and noncullin proteins, increased ubiquitinated proteins, and stabilized a surrogate substrate of the proteasome in the heart. Autophagic flux was significantly decreased, whereas autophagosomes were markedly increased in CSN8(CKO) hearts, indicative of impaired autophagosome removal. Furthermore, we observed increased oxidized proteins, massive necrotic cardiomyocytes, and morphological and functional changes characteristic of dilated cardiomyopathy in CSN8(CKO) mice. CONCLUSIONS: CSN deneddylates substrates more than cullins and is indispensable to cardiomyocyte survival in not only perinatal hearts but also adult hearts. CSN8/CSN regulates both proteasome-mediated proteolysis and the autophagic-lysosomal pathway, critical to the removal of oxidized proteins in the heart.
BACKGROUND: The COP9 signalosome (CSN) is an evolutionarily conserved protein complex composed of 8 unique protein subunits (CSN1 through CSN8). We have recently discovered in perinatal mouse hearts that CSN regulates not only proteasome-mediated proteolysis but also macroautophagy. However, the physiological significance of CSN in a post-mitotic organ of adult vertebrates has not been determined. We sought to study the physiological role of CSN8/CSN in adult mouse hearts. METHODS AND RESULTS:Csn8 was conditionally ablated in the cardiomyocytes of adult mice (CSN8(CKO)) using a temporally controlled Cre-LoxP system. Loss of CSN8 accumulated the neddylated forms of cullins and noncullin proteins, increased ubiquitinated proteins, and stabilized a surrogate substrate of the proteasome in the heart. Autophagic flux was significantly decreased, whereas autophagosomes were markedly increased in CSN8(CKO) hearts, indicative of impaired autophagosome removal. Furthermore, we observed increased oxidized proteins, massive necrotic cardiomyocytes, and morphological and functional changes characteristic of dilated cardiomyopathy in CSN8(CKO) mice. CONCLUSIONS:CSN deneddylates substrates more than cullins and is indispensable to cardiomyocyte survival in not only perinatal hearts but also adult hearts. CSN8/CSN regulates both proteasome-mediated proteolysis and the autophagic-lysosomal pathway, critical to the removal of oxidized proteins in the heart.
Authors: T Kawakami; T Chiba; T Suzuki; K Iwai; K Yamanaka; N Minato; H Suzuki; N Shimbara; Y Hidaka; F Osaka; M Omata; K Tanaka Journal: EMBO J Date: 2001-08-01 Impact factor: 11.598
Authors: D S Sohal; M Nghiem; M A Crackower; S A Witt; T R Kimball; K M Tymitz; J M Penninger; J D Molkentin Journal: Circ Res Date: 2001-07-06 Impact factor: 17.367
Authors: S Lyapina; G Cope; A Shevchenko; G Serino; T Tsuge; C Zhou; D A Wolf; N Wei; A Shevchenko; R J Deshaies Journal: Science Date: 2001-05-03 Impact factor: 47.728
Authors: Sawa Kostin; Lieven Pool; Albrecht Elsässer; Stefan Hein; Hannes C A Drexler; Eyal Arnon; Yukihiro Hayakawa; René Zimmermann; Erwin Bauer; Wolf-Peter Klövekorn; Jutta Schaper Journal: Circ Res Date: 2003-03-20 Impact factor: 17.367