Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Cell. 2017 Jul 27;170(3):492-506.e14. doi: 10.1016/j.cell.2017.06.042.
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.
干扰素-α（IFNα）信号通路对于通过诱导干扰素刺激基因（ISGs）的抗病毒反应至关重要。通过对 IFNα介导的抑制乙型肝炎病毒（HBV）复制的细胞模型中的 711 种已知表观遗传修饰物进行无偏的高通量 RNAi 筛选，我们鉴定出甲基转移酶 SETD2 是 IFNα 介导的抗病毒免疫的关键放大因子。具有肝细胞特异性 Setd2 缺失的条件敲除小鼠表现出增强的 HBV 感染。在机制上，SETD2 通过其甲基转移酶活性直接介导 STAT1 赖氨酸 525 的甲基化，从而增强 IFN 激活的 STAT1 磷酸化和抗病毒细胞反应。此外，SETD2 选择性地催化一些 ISGs 启动子上的 H3K36 的三甲基化，导致基因激活。我们的研究确定了甲基转移酶 SETD2 催化的 STAT1 赖氨酸 525 甲基化是 IFNα 依赖性抗病毒免疫的必需信号事件，并表明 SETD2 在控制病毒感染方面具有潜力。
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