Interferon-α (IFNα) signaling is essential for antiviral response via induction of IFN-stimulated genes (ISGs). Through a non-biased high-throughput RNAi screening of 711 known epigenetic modifiers in cellular models of IFNα-mediated inhibition of HBV replication, we identified methyltransferase SETD2 as a critical amplifier of IFNα-mediated antiviral immunity. Conditional knockout mice with hepatocyte-specific deletion of Setd2 exhibit enhanced HBV infection. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response. In addition, SETD2 selectively catalyzes the tri-methylation of H3K36 on promoters of some ISGs such as ISG15, leading to gene activation. Our study identifies STAT1 methylation on K525 catalyzed by the methyltransferase SETD2 as an essential signaling event for IFNα-dependent antiviral immunity and indicates potential of SETD2 in controlling viral infections.

中文翻译：

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STAT1的甲基转移酶SETD2介导的甲基化对于干扰素的抗病毒活性至关重要。

干扰素-α（IFNα）信号对于通过诱导IFN刺激的基因（ISG）进行抗病毒应答至关重要。通过对IFNα介导的HBV复制抑制的细胞模型中的711种已知表观遗传修饰子进行无偏高通量RNAi筛选，我们确定了甲基转移酶SETD2是IFNα介导的抗病毒免疫的关键扩增子。肝细胞特异性缺失Setd2的条件敲除小鼠表现出增强的HBV感染。从机制上讲，SETD2通过其甲基转移酶活性直接介导赖氨酸525上的STAT1甲基化，从而增强IFN激活的STAT1磷酸化和抗病毒细胞应答。此外，SETD2在某些ISG（例如ISG15）的启动子上选择性催化H3K36的三甲基化，从而导致基因激活。