IRF1 promotes innate immune response to viral infection through enhancing the activation of IRF3.

Innate immunity is the essential way for host cells to resist viral infection through the production of IFNs and proinflammatory cytokines. IRF3 plays a critical role in innate immune response to viral infection. However, the role of IRF1 in innate immunity remains largely unknown. In this study, we found that IRF1 is upregulated through IFN/JAK/STAT signaling pathway upon viral infection. Silencing IRF1 attenuates innate immune response to viral infection. IRF1 interacts with IFR3 and augments the activation of IRF3 through blocking the interaction between IRF3 and PP2A. DNA binding domain (DBD) of IRF1 is the key functional domain for its interaction with IRF3. Overall, our study reveals a novel mechanism of by which IRF1 promotes innate immune response to viral infection through enhancing the activation of IRF3, thereby inhibiting viral infection.IMPORTANTCE Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. IRF3 plays a critical role in innate immune response to RNA viral infection. However, whether IRF1 plays a role in innate immunity is unclear. In this study, we demonstrated that IRF1 promotes innate immune response to viral infection. IRF1 is induced by viral infection. Notably, IRF1 targets and augments the phosphorylation of IRF3 through blocking the interaction between IRF3 and PP2A, leading to upregulation of innate immunity. Collectively, our study provides new insight into the regulatory mechanism of IFN signaling and uncovers the role of IRF1 in the positive regulation of innate immune response to viral infection.