Interferon regulatory factor 3 (IRF3) is a key transcription factor in the type I interferon signaling. Its activation must be tightly controlled to efficiently activate innate immunity while avoiding its overactivation. However, the precise regulation of IRF3 and the underlying mechanisms remain unclear.
In a study published in PNAS, a research group led by Prof. XIAO Wuhan from the Institute of Hydrobiology of the Chinese Academy of Sciences identified SET and MYND domain containing protein 3 (SMYD3) as a negative regulator of the type I interferon signaling pathway, and that SMYD3 directly catalyzes the dimethylation of IRF3 at lysine 39.
Researchers first discovered that SMYD3 negatively regulated innate antiviral responses induced by both RNA and DNA viruses, and the suppressive role of SMYD3 in antiviral innate immunity depended on its enzymatic activity. The knockout of SMYD3 or the inhibition of its enzymatic activity enhanced antiviral gene expression and inhibited viral replication.
Moreover, researchers revealed that SMYD3 interacted with IRF3 to catalyze the dimethylation of IRF3 at lysine 39. This dimethylation inhibited IRF3's phosphorylation, dimerization, and subsequent nuclear translocation, ultimately suppressing IRF3 activation and downstream type I interferon signaling. The dimethylation of IRF3 at lysine 39 was increased upon viral infection, and the methylation of IRF3 at lysine 39 resulted in the loss of its activity.
To validate their findings, researchers used mouse and zebrafish as in vivo models, and they confirmed that Smyd3 deficiency in both mouse and zebrafish renders them more resistant to viral infection compared to their wild-type siblings.
This study uncovers the role of the lysine methyltransferase SMYD3 in regulating antiviral innate immunity, and provides new insight into the novel modulation of IRF3 that affects its activation.
