title: Hepatic deficiency of COP9 signalosome subunit 8 induces ubiquitin-proteasome system impairment and Bim-mediated apoptosis in murine livers.
abstract: The COP9 signalosome (CSN), an evolutionally highly conserved protein complex composed of 8 unique subunits (CSN1 through CSN8) in higher eukaryotes, is purported to modulate protein degradation mediated by the ubiquitin-proteasome system (UPS) but this has not been demonstrated in a critical mitotic parenchymal organ of vertebrates. Hepatocyte-specific knockout of the Cops8 gene (HS-Csn8KO) was shown to cause massive hepatocyte apoptosis and liver malfunction but the underlying mechanism remains unclear. Here, we report that Csn8/CSN exerts profound impacts on hepatic UPS function and is critical to the stability of the pro-apoptotic protein Bim. Significant decreases in CIS (cytokine-inducible Src homology 2 domain-containing protein), a Bim receptor of a cullin2-based ubiquitin ligase, were found to co-exist with a marked increase of Bim proteins. Csn8 deficiency also significantly decreased 19S proteasome subunit Rpt5 and markedly increased high molecular weight neddylated and ubiquitinated proteins. The use of a surrogate UPS substrate further reveals severe impairment of UPS-mediated proteolysis in HS-Csn8KO livers. Inclusion body-like materials were accumulated in Csn8 deficient hepatocytes. In addition to Bim, massive hepatocyte apoptosis in HS-Csn8KO livers is also associated with elevated expression of other members of the Bcl2 family, including pro-apoptotic Bax as well as anti-apoptotic Bcl2 and Bcl-XL. Increased interaction between Bcl2 and Bim, but not between Bcl2 and Bax, was detected. Hence, it is concluded that hepatic CSN8 deficiency impairs the UPS in the liver and the resultant Bim upregulation likely plays an important role in triggering hepatocyte apoptosis via sequestering Bcl2 away from Bax.
authors.affiliation: Division of Basic Biomedical Sciences, The University of South Dakota Sanford School of Medicine, Vermillion, South Dakota, United States of America.
authors.forename: Daoxiong
authors.initials: D
authors.lastname: Lei
authors.forename: Faqian
authors.initials: F
authors.lastname: Li
authors.forename: Huabo
authors.initials: H
authors.lastname: Su
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Wei
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D000075686:COP9 Signalosome Complex; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D000075687:NEDD8 Protein; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; C481538:Cops8 protein, mouse; D008565:Membrane Proteins; D000075687:NEDD8 Protein; C513172:Nedd8 protein, mouse; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D014452:Ubiquitins; D000075686:COP9 Signalosome Complex; D046988:Proteasome Endopeptidase Complex