Activation of the transcription factor IRF3, a central regulator of type I interferon signaling, is induced through the phosphorylation of serine and threonine residues in the transactivation domain of IRF3, followed by dimerization of IRF3 and its translocation to the nucleus. In Immunity, Xie and colleagues show that deactivation of IRF3 after activation induced by the RNA helicase RIG-I, TLR3 or TLR4 is regulated through dephosphorylation by the phosphatase PP2A. The interaction between IRF3 and PP2A is mediated by the adaptor RACK1, which mediates the formation of an IRF3-RACK1-PP2A complex and promotes the dephosphorylation of IRF3 at steady state. Sendai virus and ligands of TLR3 and TLR4 induce transient dissociation of IRF3 from this complex and translocation of IRF3 to the nucleus. Although high viral titers trigger degradation of IRF3, stimulation with a low titer of virus and TLR ligands induces dephosphorylation of IRF3, which suggests that cells recycle this transcription factor.

Immunity 40, 515–529 (2014)