Abstract: During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cyclic guanosine monophosphate-adenosine monophosphate synthase, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here, we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases inhibitor of nuclear factor κB subunit IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.
