Porcine IRF2 suppresses the cGAS-STING-mediated antiviral IFN signaling by competing IRF3 for binding to the IFN promoter

The innate immune cGAS-STING-IRF3-IFN signaling pathway plays a crucial role in host antiviral defense. While mammalian IRF families encompass IRF1 through IRF9, the involvement of IRF members other than IRF3 in cGAS-STING antiviral signaling transduction and/or regulation remains poorly characterized. Through dual screening systems, we identified the porcine (p) IRF2 as a potent suppressor of porcine cGAS-STING-IFN antiviral signaling. First, we demonstrate that pIRF2 suppresses both cGAS-STING- and TBK1/IKKε/IRF3-activated IFN signaling. Further, we reveal that pIRF2 does not affect STING-activated IRF3 phosphorylation, nor does it impair IRF3 dimerization or nuclear translocation. The inhibitory activity of pIRF2 depends on its DNA binding domain (DBD) but not IRF-associated domain (IAD). Importantly, we find that pIRF2 directly binds the IFN-β promoter and competes IRF3 for binding to IFN-β promoter. In summary, our findings unveil a distinct function of pIRF2 as well as the regulatory mechanism governing porcine cGAS-STING-IFN antiviral function.