Hu Ming-Ming, Liao Chen-Yang, Yang Qing, Xie Xue-Qin, Shu Hong-Bing
Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan 430071, China.
Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan 430071, China
J Exp Med. 2017 Apr 3;214(4):973-989. doi: 10.1084/jem.20161015. Epub 2017 Mar 1.
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.
胞质受体视黄酸诱导基因I（RIG-I）和黑色素瘤分化相关基因5（MDA5）对病毒RNA的感知会引发先天性抗病毒反应。RIG-I和MDA5在先天性抗病毒反应中如何受到动态调控尚不清楚。在此，我们表明TRIM38正向调节MDA5和RIG-I介导的下游基因诱导，并作为一种SUMO E3连接酶，分别在病毒感染前后对其在K43/K865和K96/K888位点进行动态SUMO化修饰。MDA5和RIG-I的SUMO化修饰可抑制它们在未感染或早期感染细胞中发生的K48连接的多聚泛素化和降解。MDA5和RIG-I的半胱天冬酶募集结构域的SUMO化修饰对于它们被PP1去磷酸化以及在病毒感染时被激活也是必需的。在病毒感染后期，MDA5和RIG-I都被SENP2去SUMO化，导致它们发生K48连接的多聚泛素化和降解。这些发现表明，MDA5和RIG-I的动态SUMO化和去SUMO化调节了对RNA病毒的有效先天性免疫及其适时终止。
