A new study has identified SET domain-containing lysine methyltransferase 7 (SET7) as a critical negative regulator of antiviral innate immunity. It found that SET7 directly catalyzes the monomethylation of interferon regulatory factor 3 (IRF3) at lysine 98, which potently suppresses IRF3 activation.

The study, published recently in the Proceedings of the National Academy of Sciences (PNAS), was conducted by a research group led by Prof. XIAO Wuhan from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences. 

IRF3 is a key transcription factor that governs antiviral innate immunity. Upon viral infection, the upstream signaling cascade activates TANK Binding Kinase 1 (TBK1), which subsequently mediates the phosphorylation of IRF3. This process triggers IRF3 dimerization and subsequent nuclear translocation, ultimately driving the production of type I interferons (IFNs). IRF3 activity is tightly controlled by diverse post-translational modifications (PTMs). Nevertheless, the regulatory role of methylation in IRF3 function remains incompletely understood.

In this study, the researchers found that SET7 attenuates the host antiviral immune response in an enzymatic activity-dependent manner. During infection with either RNA or DNA viruses, genetic disruption of SET7 or pharmacological inhibition of its methyltransferase activity enhanced antiviral gene expression and inhibited viral replication.

Mechanistically, the researchers found that SET7 interacts with IRF3 and catalyzes its monomethylation at lysine 98. This methylation decreases IRF3 phosphorylation, dimerization, and subsequent nuclear translocation, thereby inhibiting the production of downstream type I interferons.

Using mice and zebrafish as in vivo models, the researchers found that SET7-deficient mice and zebrafish showed significantly enhanced resistance to viral infection.

According to the researchers, this study identifies a previously unrecognized post-translational modification of IRF3 that modulates its activation and reveals a novel biological function of SET7 in innate antiviral immune regulation. Importantly, the findings suggest that SET7 may serve as a potential molecular target for breeding new fish strains with enhanced resistance to viral infection.

The working model of SET7 in antiviral innate immunity. (Image by IHB)