Regulation Of IFNα-mediated Antiviral Activity By Histone Methyltransferase SETD2 And The Underlying Mechanisms

Type Ⅰ Interferon(IFN-I)signaling is essential for host defense.against viral infections via induction of IFN-stimulated genes(ISGs).However,dysregulation of IFNs signaling could mediate immune pathogenesis such as inflammatory autoimmune diseases and infectious diseases via aberrantly activating inflammatory responses.Thus,IFN responses need to be tightly regulated to achieve protective immunity against infection while avoiding harmful toxicity caused by improper or prolonged IFN signaling.Multiple levels of cellular and molecular events act in a cooperated manner to regulate IFN responses.However,how post-translational modification and epigenetic regulation,two processes closely linked to important biological and pathological processes regulate IFNa-mediated antiviral responses remain unclear.In this study,we performed a non-biased high-throughput RNAi screening of 711 known epigenetic modifiers in cellular models of IFNa-mediated inhibition of HBV replication.We identified the methyltransferase SETD2 as a critical modulator of IFNa-mediated antiviral immunity.Conditional knockout mice with hepatocyte specific deletion of Setd2 exhibit the exaggerated HBV infection.Mechanistically,SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity,which reinforces IFNa-activated STAT1 phosphorylation and the antiviral cellular response.In addition,SETD2 selectively catalyzes the tri-methylation of H3K36 on distal promoters of some ISGs including ISG15 and IP-10,leading to gene activation and induces a newly identified ISG RARRES3 to inhibit HBV infection.Our study identifies STAT1 methylation on K525 catalyzed by methyltransferase SETD2 as an essential signaling event for IFNa-dependent antiviral immunity.In addition,our study reveals that the non-histone methylation function of SETD2 is important for regulation of antiviral immunity of IFN.Besides,mimicking the activity of SETD2 may lead to novel therapeutic strategies for virally infectious diseases.