The transcription factor IRF3 is a central regulator of type I interferon (IFN) signaling. The mechanisms underlying deactivation of IRF3 are poorly understood although many studies suggest that IRF3 activity is terminated through degradation after viral infection. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. After challenge with LPS, poly(I:C), or low-titer SeV, activated IRF3 was dephosphorylated and returned to resting state without being degraded, although high-titer SeV infection triggered the degradation of IRF3. Furthermore, PP2A-deficient macrophages showed enhanced type I IFN signaling upon LPS, poly(I:C), and SeV challenge and protected mice from lethal vesicular stomatitis virus infection. Therefore, dephosphorylation of IRF3 is a deactivation mechanism that contributes to termination of IRF3-type I IFN signaling.
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