NDR2 promotes the antiviral immune response via facilitating TRIM25-mediated RIG-I activation in macrophages
NDR2 promotes the antiviral immune response via facilitating TRIM25-mediated RIG-I activation in macrophages
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NDR2 通过促进巨噬细胞中 TRIM25 介导的 RIG-I 激活来促进抗病毒免疫反应
DOI：
10.1126/sciadv.aav0163
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发表时间：
2019-02-01
期刊：
影响因子：
13.6
通讯作者：
Wang, Xiaojian
中科院分区：
文献类型：
--
作者：
Liu, Zhiyong;Wu, Cheng;Wang, Xiaojian
视黄酸诱导基因I（RIG-I）是一种重要的细胞质感受器，识别病毒RNA启动抗病毒天然免疫。然而，RIG-I信号转导的翻译后调节还没有很好地理解。我们在这里报告，核Dbf 2相关激酶2（NDR 2）的功能作为一个重要的正调节RIG-I介导的抗病毒免疫反应。NDR 2或其激酶失活突变体的过表达增强RNA病毒诱导的I型干扰素和促炎细胞因子的产生并抑制病毒复制。NDR 2条件性敲除小鼠（Lysm（+）NDR 2（f/f））显示抗病毒免疫应答受损。在机制上，NDR 2直接与RIG-I和TRIM 25结合，从而促进RIG-I/TRIM 25复合物并增强TRIM 25介导的RIG-I的K63连接的多聚泛素化，这是RIG-I介导的抗病毒免疫应答所需的。此外，NDR 2表达在呼吸道合胞病毒感染患者的外周血和病毒感染的巨噬细胞中显著下调。总的来说，这些发现提供了深入了解NDR 2在抗病毒免疫中的功能及其相关的临床意义。
Retinoic acid-inducible gene I (RIG-I), a pivotal cytosolic sensor, recognizes viral RNAs to initiate antiviral innate immunity. However, posttranslational regulation of RIG-I signaling is not well understood. We report here that nuclear Dbf2-related kinase 2 (NDR2) functions as a crucial positive regulator of the RIG-I-mediated antiviral immune response. Overexpression of NDR2 or its kinase-inactive mutants potentiates RNA virus-induced production of type I interferons and proinflammatory cytokines and dampens viral replication. NDR2 conditional knockout mice (Lysm(+)NDR2(f/f)) show an impaired antiviral immune response. Mechanistically, NDR2 directly associates with RIG-I and TRIM25, thus facilitating the RIG-I/TRIM25 complex and enhancing the TRIM25-mediated K63-linked polyubiquitination of RIG-I, which is required for the RIG-I-mediated antiviral immune response. Furthermore, NDR2 expression is notably down-regulated in peripheral blood from respiratory syncytial virus-infected patients and in virus-infected macrophages. Collectively, these findings provide insights into the function of NDR2 in antiviral immunity and its related clinical significance.