Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity
Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity
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DOI：
10.1016/j.cell.2017.06.042
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发表时间：
2017-07-27
期刊：
影响因子：
64.5
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Chen, Kun;Liu, Juan;Cao, Xuetao
干扰素- α (IFN α)信号通过诱导干扰素刺激基因（isg）对抗病毒反应至关重要。通过对IFN α介导的HBV复制抑制细胞模型中711种已知表观遗传修饰因子的无偏倚高通量RNAi筛选，我们确定甲基转移酶SETD2是IFN α介导的抗病毒免疫的关键放大器。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。在机制上，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反应。此外，SETD2选择性地催化一些isg（如ISG15）启动子上H3K36的三甲基化，导致基因活化。我们的研究发现，由甲基转移酶SETD2催化的K525上的STAT1甲基化是IFN α依赖性抗病毒免疫的重要信号事件，并表明SETD2在控制病毒感染方面的潜力。
Interferon-alpha (IFN alpha) 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 IFN alpha-mediated inhibition of HBV replication, we identified methyltransferase SETD2 as a critical amplifier of IFN alpha-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 IFN alpha-dependent antiviral immunity and indicates potential of SETD2 in controlling viral infections.