Rig-G negatively regulates SCF-E3 ligase activities by disrupting the assembly of COP9 signalosome complex

• Published in: Biochemical and biophysical research communications Vol. 432; no. 3; pp. 425 - 430
• Main Authors: Xu, Gui-Ping, Zhang, Zhang-Lin, Xiao, Shu, Zhuang, Li-Kun, Xia, Di, Zou, Qing-Ping, Jia, Pei-Min, Tong, Jian-Hua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.03.2013
• Subjects: Cell Line, Tumor; COP9 Signalosome Complex; CRL; CSN complex; Cullin Proteins - metabolism; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Multiprotein Complexes - metabolism; Neddylation; Peptide Hydrolases - metabolism; Rig-G; SCF-E3 ligase; SKP Cullin F-Box Protein Ligases - metabolism; Ubiquitination; SCF-E3 ligase; Neddylation; CRL3; Ub; IFN; Ubiquitination; CAND1; SCF; ATRA; CRL; Rig-G; CSN; CSN complex
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2013.01.132

► Rig-G is a key mediator of the antiproliferative activity of IFN-related pathway. ► Rig-G can interfere with the integrity and the stability of CSN complex. ► Rig-G impairs the CSN complex-mediated deubiquitination and deneddylation. ► Rig-G negatively regulates SCF-E3 ligase activities by disassembling CSN complex. ► We report that Rig-G is involved in the regulation of CRL-E3 activities. 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.