Direct lysine dimethylation of IRF3 by the methyltransferase SMYD3 attenuates antiviral innate immunity

Interferon regulatory factor 3 (IRF3) is the key transcription factor in the type I IFN signaling pathway, whose activation is regulated by multiple posttranslational modifica_x0002_tions. Here, we identify SMYD3, a lysine methyltransferase, as a negative regulator of IRF3. SMYD3 interacts with IRF3 and catalyzes the dimethylation of IRF3 at lysine 39. This modification reduces IRF3 phosphorylation, dimerization, and subsequent nuclear translocation, leading to the inhibition of downstream type I interferon production. In addition, Smyd3-deficient mice are more resistant to RNA and DNA viral infections. Zebrafish lacking smyd3 or treated with the inhibitor BCI121 are also more resistant to viral infection. Our findings reveal a role for SMYD3 in the regulation of antiviral innate immunity and provide insight into a unique modulation of IRF3 that affects its activation. Whole RNA from MEF cells infected with VSV was purified using the RNeasy Mini Kit (QIAGEN, #74104). To ensure the quality of the information analysis, fastp software was used to remove the splice sequences, filter the low quality, N bases (indicating that the base information could not be determined), and obtain high quality clean data. The clean data and the number of bases and sequences of the clean data were counted. At the same time, the GC, Q20, Q30 contents of the clean data were calculated (Benagen Technology, Wuhan, China). Volcano Plot were generated using the ggplot2 software. Heatmaps were generated using the Multi Experiment Viewer (MeV) software. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses for the differentially expressed genes (DEGs) was performed using Cluster Profiler version 3.8.