title: c-Cbl-mediated ubiquitination of IRF3 negatively regulates IFN-β production and cellular antiviral response.
abstract: Induction of type I interferon is a fundamental cellular response to viral infection. Interferon regulatory factor 3 (IRF3) plays an essential role in Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I) mediated induction of type I interferon and host antiviral responses. However, posttranslational regulation of IRF3 remains to be fully understood. In this study, we identified E3 ubiquitin ligase Casitas B-lineage lymphoma (c-Cbl) as a negative regulator for IRF3 protein stability and IFN-β signal pathway. Knockdown of c-Cbl expression by small interfering RNA enhanced virus-induced IFN-β production as well as cellular antiviral response, whereas overexpression of c-Cbl inhibited virus-induced IFN-β signaling. Coimmunoprecipitation experiments demonstrated that c-Cbl interacted with IRF3 via TKB domain of c-Cbl and IRF association domain of IRF3, promoting K48-linked polyubiquitination and proteasomal degradation of IRF3. Therefore, our findings suggest that c-Cbl negatively regulates IFN-β signaling and cellular antiviral response by promoting IRF3 ubiquitination and degradation, providing a new mechanism for control of type I interferon induction.
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors: Xibao
authors: X
authors: Zhao
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors: Huihui
authors: H
authors: Zhu
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors: Juan
authors: J
authors: Yu
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors: Hongrui
authors: H
authors: Li
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors: Jiafeng
authors: J
authors: Ge
authors: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: cwl@zju.edu.cn.
authors: Weilin
authors: W
authors: Chen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000096:biosynthesis*; D008239:Lysine / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D014158:Transcription, Genetic; D054875:Ubiquitination
chemical_list: D000998:Antiviral Agents; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D050721:Proto-Oncogene Proteins c-cbl; D046988:Proteasome Endopeptidase Complex; D008239:Lysine
keywords: Antiviral response; IRF3; Ubiquitination; c-Cbl