c-Cbl-mediated ubiquitination of IRF3 negatively regulates IFN-β production and cellular antiviral response

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.