PNAS：曹雪涛院士、张纪岩研究员PNAS发布重要免疫成果

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来自中国医学科学院、军事医学科学院的研究人员证实，RNF122通过靶向RIG-I CARDs介导RIG-I降解，抑制了抗病毒I型干扰素生成。这一研究发现发布在8月9日的《美国国家科学院院刊》（PNAS）上。我国著名的免疫学家曹雪涛（Xuetao Cao）院士和军事医学科学院基础医学研究所的张纪岩(Jiyan Zhang)研究员是这篇论文的共同通讯作者。

在这篇PNAS新文章中，曹雪涛、张纪岩和合著作者们指出，病毒RNA的细胞质天然感受器RIG-I受到严格地调控，以适当维持免疫稳态，在启动天然抗病毒反应有效清除RNA病毒之外防止过度的炎症反应。一些翻译后修饰，尤其是泛素化对于调控RIG-I的活性至关重要。越来越多的证据表明，E3连接酶在各种细胞过程，包括细胞增殖和天然抗病毒信号中发挥重要作用。

在这里，他们通过在RNA病毒感染细胞中质谱法筛查RIG-I互作蛋白，确定了E3泛素连接酶RNF122直接与小鼠RIG-I发生了互作。RNF122的跨膜结构域结合了RIG-I的半胱氨酸天冬酰胺特异蛋白酶活化募集结构域(caspase activation and recruitment domains，CARDs) ；这种互作有效地触动了RNF122的RING finger结构域，将Lys-48连接的泛素传递至RIG-I CARDs的Lys115和Lys146残基上，促进了RIG-I降解，导致RIG-I下游信号显著受到抑制。

研究人员证实RNF122在各种免疫细胞中广泛表达，其优先表达于巨噬细胞中。RNF122缺陷可选择性提高巨噬细胞中RIG-I触动的I型IFNs和促炎症细胞因子生成。RNF122缺陷小鼠I型IFNs生成增高，更加抵抗致命性RNA感染。

因此，研究结果证实了RNF122通过靶向RIG-I的CARDs，介导蛋白酶体降解RIG-I，充当了RIG-I触发天然抗病毒反应的一个选择性负调控因子。

新研究概述了E3连接酶调控天然感受器RIG-I天然抗病毒免疫的一条途径。

来源：生物通

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RNF122 suppresses antiviral type I interferon production by targeting RIG-I CARDs to mediate RIG-I degradation

Wendie Wanga,1, Minghong Jianga,1, Shuo Liua, Shikun Zhanga, Wei Liua, Yuanwu Mab, Lianfeng Zhangb, Jiyan Zhangc,2, and Xuetao Cao

The activation of retinoic acid-inducible gene 1 (RIG-I), a cytoplasmic innate sensor for viral RNA, is tightly regulated to maintain immune homeostasis properly and prevent excessive inflammatory reactions other than initiation of antiviral innate response to eliminate RNA virus effectively. Posttranslational modifications, particularly ubiquitination, are crucial for regulation of RIG-I activity. Increasing evidence suggests that E3 ligases play important roles in various cellular processes, including cell proliferation and antiviral innate signaling. Here we identify that E3 ubiquitin ligase RING finger protein 122 (RNF122) directly interacts with mouse RIG-I through MS screening of RIG-I–interacting proteins in RNA virus-infected cells. The transmembrane domain of RNF122 associates with the caspase activation and recruitment domains (CARDs) of RIG-I; this interaction effectively triggers RING finger domain of RNF122 to deliver the Lys-48–linked ubiquitin to the Lys115 and Lys146 residues of RIG-I CARDs and promotes RIG-I degradation, resulting in a marked inhibition of RIG-I downstream signaling. RNF122 is widely expressed in various immune cells, with preferential expression in macrophages. Deficiency of RNF122 selectively increases RIG-I–triggered production of type I IFNs and proinflammatory cytokines in macrophages. RNF122-deficient mice exhibit more resistance against lethal RNA virus infection, with increased production of type I IFNs. Thus, we demonstrate that RNF122 acts as a selective negative regulator of RIG-I–triggered antiviral innate response by targeting CARDs of RIG-I and mediating proteasomal degradation of RIG-I. Our study outlines a way for E3 ligase to regulate innate sensor RIG-I for the control of antiviral innate immunity.

http://www.pnas.org/content/113/34/9581.long