The structural basis of IRF-3 recruitment, activation, and targeting in innate immunity

Abstract

Abstract Type I interferons (IFNs) are key cytokines mediating innate antiviral immunity. cGAS, RLRs, and TLRs recognize microbial DNA, RNA, and LPS to induce the expression of type I IFNs. These signaling pathways converge at the recruitment and activation of IRF-3. STING, MAVS, and TRIF mediate the recruitment of IRF-3 through a conserved pLxIS motif. Here we show that the pLxIS motif of phosphorylated STING, MAVS, and TRIF binds to IRF-3 in a similar manner, while residues upstream of the motif confer specificity. The structure of IRF-3 phosphomimetic mutant S386/396E bound to CBP reveals that the pLxIS motif also mediates IRF-3 dimerization and activation. Moreover, rotavirus NSP1 employs a pLxIS motif to target IRF-3 for degradation. However, phosphorylation of NSP1 is not required for its activity. These results suggest a concerted mechanism for recruitment and activation of IRF-3 that can be subverted by viral proteins to evade innate immune response.