Innate immunity to RNA virus is regulated by temporal and reversible sumoylation of RIG-I and MDA5.
Innate immunity to RNA virus is regulated by temporal and reversible sumoylation of RIG-I and MDA5.
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对 RNA 病毒的先天免疫受 RIG-I 和 MDA5 的暂时且可逆的 sumoylation 调节
DOI：
10.1084/jem.20161015
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发表时间：
2017-04-03
期刊：
影响因子：
--
通讯作者：
Shu HB
中科院分区：
文献类型：
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作者：
Hu MM;Liao CY;Yang Q;Xie XQ;Shu HB
通过胞质受体RIG-I和黑素瘤分化相关基因5（MDA 5）感测病毒RNA导致先天性抗病毒应答。RIG-I和MDA 5在先天性抗病毒反应中如何动态调节尚不清楚。在这里，我们发现TRIM 38正调控MDA 5和RIG-I介导的下游基因的诱导，并作为SUMO E3连接酶，分别在病毒感染前后在K43/K865和K96/K888处进行动态类小泛素化。MDA 5和RIG-I的SUMO化抑制了它们在未感染或早期感染细胞中的K48连接的多聚泛素化和降解。MDA 5和RIG-I的半胱天冬酶募集结构域的类小泛素化也是其通过PP 1去磷酸化和在病毒感染时活化所必需的。在病毒感染的晚期，MDA 5和RIG-I都被SENP 2去小泛素化，导致它们的K48连接的多聚泛素化和降解。这些发现表明，MDA 5和RIG-I的动态SUMO化和去SUMO化调节对RNA病毒的有效先天免疫及其及时终止。
Sensing of viral RNA by the cytosolic receptors RIG-I and melanoma differentiation-associated gene 5 (MDA5) leads to innate antiviral response. How RIG-I and MDA5 are dynamically regulated in innate antiviral response is not well understood. Here, we show that TRIM38 positively regulates MDA5- and RIG-I–mediated induction of downstream genes and acts as a SUMO E3 ligase for their dynamic sumoylation at K43/K865 and K96/K888, respectively, before and after viral infection. The sumoylation of MDA5 and RIG-I suppresses their K48-linked polyubiquitination and degradation in uninfected or early-infected cells. Sumoylation of the caspase recruitment domains of MDA5 and RIG-I is also required for their dephosphorylation by PP1 and activation upon viral infection. At the late phase of viral infection, both MDA5 and RIG-I are desumoylated by SENP2, resulting in their K48-linked polyubiquitination and degradation. These findings suggest that dynamic sumoylation and desumoylation of MDA5 and RIG-I modulate efficient innate immunity to RNA virus and its timely termination.