Phosphorylation of Ser82 on IRF3 acts as negative-feedback regulation of IRF3-dependent innate immunity

Interferon Regulatory Factor 3 (IRF3) is essential for the production of type I interferon (IFN) during virus infection; however, the mechanism underlying its regulation remains to be elucidated. Here we have identified a novel negative regulatory phosphorylation site on IRF3. In this study, we discovered that Ser82 phosphorylation on IRF3 abrogates virus-induced IFN-β activation. Furthermore, our results clarified the mechanism in which Ser82 phosphorylation on IRF3 retains the function of dimerization and nuclear import, but abolishes the promoter binding ability of IRF3. In addition, Ser82 phosphorylation on IRF3 serves as a negative feedback mechanism for the type I IFN response. These findings elucidate a previously unknown mechanism for negatively regulating IRF3 to finely tune type I IFN response. •Phosphorylation of Ser82 on IRF3 acts as a negative regulation mechanism for the activation of IRF3.•The negative regulatory mechanism underlying Ser82 phosphorylation on IRF3 lies in its control on IR promoter binding of IRF3.•Phosphorylation of Ser82 on IRF3 serves as a negative feedback mechanism for the type I IFN response.