MEKK2 Negatively Regulates IRF3-mediated Innate Antiviral Immunity

Innate immunity is the first line of host defense against pathogen invasion,in which the IFN-I mediated anti-viral response plays an important role in the process of resisting virus infection and maintaining self-stability.Protein phosphorylation is one of the most important post-translational modification types.Protein kinase regulates substrate activity by phosphorylating,and plays an important role in signal transduction of innate immune.After virus infection,the host recognizes the pathogen-associated molecular patterns(PAMPs)by pathogen recognition receptors(PRRs),then recruits and activates a series of downstream kinases to form a signal cascade,which induces the production of IFN-I and activates the antiviral response.The transcription factor IRF3 is an important regulator in the IFN-I signalling,which is activated by kinase TBK-1/IKK?.The transcription activity of IRF3 is crucial for the production of IFN-I,which must be regulated to maintain the immune homeostasis.It is well known that the activation of IRF3 requires phosphorylation of multiple Ser/Ter sites in the c-terminal domain,but the reports of phosphorylation inhibiting IRF3 activity are sparse.Once activated,the activity of IRF3 must be switched off in time because overactive IRF3 signaling will result in unwanted issues,such as inflammatory skin disease,septic shock syndrome,or autoimmune disorders.Therefore,the regulation of IRF3 transcription activity is crucial to understand the innate antiviral immunity.Screening the kinase c DNA library,we found that MEKK2(MAP kinase kinase kinase-2,MAP3K2)could inhibit the activation of IFN-? promoter by reporter assay.We further found that MEKK2 can interact with IRF3,then inhibits the activation of IRF3 by phosphorylating Ser173 which inhibits IRF3 dimerization and the import of IRF3 into the nucleus,ultimately inhibits the production of IFN-I.In this study,we first found that Ser173 is the negative phosphorylation site of IRF3,which confirmed that the phosphorylation of Ser173 could inhibit the activation of IRF3.We have also explained the molecular mechanism that MEKK2 regulates IRF3-mediated innate antiviral immunity.This discovery greatly enriches the understanding of the regulation of IRF3 activity and the mechanism of IFN-I production,and provides new ideas for the treatment of viral infection,inflammation and autoimmune diseases.