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

SET7 is a member of the SET domain (SETD) methyltransferase family that catalyzes the monomethylation of lysine residues in histones and nonhistone proteins. This process either enhances or suppresses 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 post-translational 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, are more resistant 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.