On July 27, 2017, Prof. Xuetao Cao (Zhejiang University School of Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences) and his group published a research article in Cell about the identification of histone methyltransferase SETD2 as a critical modulator of IFN-mediated antiviral immunity (Chen K., et al., Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity. Cell (2017),170.3:492.).

Type I interferons (IFNs) is critical for host defense against viral infection via induction of IFN-stimulated genes (ISGs) through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Dysregulation of IFN signaling has been closely associated with pathogenesis of various infectious and inflammatory disorders. While the crucial role of IFN-induced signaling pathways in host antiviral responses is well established, the mechanisms for the regulation of IFN signaling and ISGs expression remain to be fully elucidated.

In this paper, Prof. Cao revealed a new function of methyltransferase SETD2 which is critical for enhancing the IFN signaling and promoting the IFN antiviral function. The author firstly performed a non-biased high-throughput RNAi screening of 711 known epigenetic modifiers for their potential roles in IFN-mediated inhibition of HBV replications and identified SETD2 as an important regulator that promotes IFN-mediated cellular response against HBV replication. Further investigation showed that SETD2 can directly bind to STAT1 and catalyze its methylation on lysine 525 residue, which consequently resulted in an enhanced phosphorylation and activation of STAT1, and higher ISGs expression. Importantly, they also found that SETD2 selectively regulated the H3K36me3 levels of some ISGs to promote their transcription induced by IFN. Thus, SETD2 enhances host antiviral immunity by strengthening IFN signaling both post-translationally and epigenetically.

Ph.D Kun Chen from Zhejiang University is the first author of this paper. Prof. Xuetao Cao is the corresponding author. This work was supported by grants from the Natural Science Foundation of China and Ministry of Science and Technology of China (973 Program).