IRX2 Negatively Regulates IRF3‐Mediated Type I Interferon and Antiviral Response

While type I interferon is critical for viral clearance in host defense, its production needs to be tightly regulated in both physiological and infectious contexts. Herein, we reported that an Iroquois homeobox protein IRX2 negatively regulates the activation of type I interferon signaling during influenza infection. We found that IRX2 binds to the IRF3 and negatively regulates IRF3 activation and IRF3-mediated interferon signaling. Knockdown of IRX2 upregulated the phosphorylation of IRF3 and augmented the production of type I interferon cytokines and antiviral immunity. We further showed that genetic abrogation of IRX2 protected mice from lethal influenza infection. Our results reveal a previously unrecognized non-transcriptional function of IRX2, and suggest a potential therapeutic target in viral infections.