YWHAZ downregulated innate immune responses to RNA viruses by inhibiting the IRF3 signaling pathway

The activation of IRF3 induced by RIG-I-like receptors is pivotal for type 1 interferon (IFN) production in antiviral immunity. Virus infection leads to type 1 IFN production through inducing the dimerization and subsequent nuclear translocation of IRF3. Following its activation, IRF3 must be tightly regulated to prevent a dysregulated or excessive immune response. Here, we first found that YWHAZ, a member of the 14-3-3 protein family, is a negative regulator of type 1 IFN production by targeting IRF3 signaling. YWHAZ is bound to IRF3 to inhibit the formation of the TBK1-IRF3 complex, the phosphorylation and dimerization of IRF3, as well as the subsequent nuclear translocation. YWHAZ also impeded the KPNA3-IRF3 interaction by binding to KPNA3, thereby inhibiting IRF3 nuclear translocation. The aa 124-184 in YWHAZ was critical for YWHAZ-mediated suppression of type 1 IFNs. These findings reveal the mechanism by which YWHAZ promotes RNA virus replication, thereby advancing our understanding of how YWHAZ mediates innate immune responses.