title: Rig-G negatively regulates SCF-E3 ligase activities by disrupting the assembly of COP9 signalosome complex.
abstract: We previously showed that Rig-G, an antiproliferative protein induced by interferon, can sequester CSN5 protein in the cytoplasm. Here, we report that Rig-G can destroy the functions of CSN5-containing COP9 signalosome (CSN), a highly conserved multiprotein complex implicated in protein deneddylation, deubiquitination, and phosphorylation. By damaging integrity and stability of the CSN complex, Rig-G can dramatically reduce the cellular content of CSN complex and inhibit its regulatory roles in assembly and activation of cullin-RING ubiquitin E3 ligases (CRL). Furthermore, Rig-G can cause excessive activation of CRL through inhibition of CSN-mediated deneddylation, largely decreasing protein levels of Cul1 and βTrCP, two important subunits of SCF (Skp1-Cul1-F-box protein)-E3 ligase. Rig-G can also attenuate the ability of CSN to recruit USP15 and impair CSN-associated deubiquitination. Increased autoubiquitination of βTrCP and concomitant accumulation of target substrates (such as IκBα) are observed in Rig-G-expressing cells. Taken together, our findings reveal for the first time the negative regulation of Rig-G on SCF-E3 ligase activities through disrupting CSN complex, not only contributing to further investigation on biological functions of Rig-G, but also leading to better understanding of the CSN complex as a potential target in tumor diagnosis and treatment.
authors: Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Gui-Ping
authors: GP
authors: Xu
authors: Zhang-Lin
authors: ZL
authors: Zhang
authors: Shu
authors: S
authors: Xiao
authors: Li-Kun
authors: LK
authors: Zhuang
authors: Di
authors: D
authors: Xia
authors: Qing-Ping
authors: QP
authors: Zou
authors: Pei-Min
authors: PM
authors: Jia
authors: Jian-Hua
authors: JH
authors: Tong
mesh_terms: D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C503645:CUL3 protein, human; D044842:Cullin Proteins; C116468:IFIT3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D044843:SKP Cullin F-Box Protein Ligases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex