SET7-mediated methylation of IRF3 at lysine 98 attenuates antiviral innate immunity.

SET7 belongs to the SET domain (SETD) methyltransferase family, which catalyzes the monomethylation of lysine residues in histones and nonhistone proteins. This process can either enhance or suppress gene activation. Interferon regulatory factor 3 (IRF3) is a key transcription factor in the type I interferon (IFN) signaling pathway. This pathway is controlled by multiple posttranslational modifications that finely tune IRF3's function. Here, we identify SET7 as a negative regulator of IRF3. SET7 interacts with IRF3 and catalyzes the monomethylation of IRF3 at lysine 98. This modification decreases IRF3 phosphorylation, dimerization, and subsequent nuclear translocation, thereby inhibiting the production of downstream type I interferons. Furthermore, zebrafish lacking set7, as well as those treated with the inhibitor (R)-PFI-2, exhibits greater resistance to viral infection. Set7-deficient mice also exhibit greater resistance to RNA and DNA viral infections. Our findings reveal a role for SET7 in regulating antiviral innate immunity and provide insight into the IRF3 monomethylation that affects its activation.