Institute of Pathogen Biology and Immunology of College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, Hunan, China.
Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
J Virol. 2017 Nov 14;91(23). doi: 10.1128/JVI.01264-17. Print 2017 Dec 1.
Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. However, attenuation or termination of signaling is also necessary for preventing immune-mediated tissue damage and spontaneous autoimmunity. Here, we identify nucleotide binding oligomerization domain (NOD)-like receptor X1 (NLRX1) as a negative regulator of the mitochondrial antiviral signaling protein (MAVS)-mediated signaling pathway during hepatitis C virus (HCV) infection. The depletion of NLRX1 enhances the HCV-triggered activation of interferon (IFN) signaling and causes the suppression of HCV propagation in hepatocytes. NLRX1, a HCV-inducible protein, interacts with MAVS and mediates the K48-linked polyubiquitination and subsequent degradation of MAVS via the proteasomal pathway. Moreover, poly(rC) binding protein 2 (PCBP2) interacts with NLRX1 to participate in the NLRX1-induced degradation of MAVS and the inhibition of antiviral responses during HCV infection. Mutagenic analyses further revealed that the NOD of NLRX1 is essential for NLRX1 to interact with PCBP2 and subsequently induce MAVS degradation. Our study unlocks a key mechanism of the fine-tuning of innate immunity by which NLRX1 restrains the retinoic acid-inducible gene I-like receptor (RLR)-MAVS signaling cascade by recruiting PCBP2 to MAVS for inducing MAVS degradation through the proteasomal pathway. NLRX1, a negative regulator of innate immunity, is a pivotal host factor for HCV to establish persistent infection. Innate immunity needs to be tightly regulated to maximize the antiviral response and minimize immune-mediated pathology, but the underlying mechanisms are poorly understood. In this study, we report that NLRX1 is a proviral host factor for HCV infection and functions as a negative regulator of the HCV-triggered innate immune response. NLRX1 recruits PCBP2 to MAVS and induces the K48-linked polyubiquitination and degradation of MAVS, leading to the negative regulation of the IFN signaling pathway and promoting HCV infection. Overall, this study provides intriguing insights into how innate immunity is regulated during viral infection.
先天免疫的激活对于宿主细胞限制入侵病毒和其他病原体的传播至关重要。然而，信号的衰减或终止对于防止免疫介导的组织损伤和自发自身免疫也是必要的。在这里，我们确定核苷酸结合寡聚化结构域（NOD）样受体 X1（NLRX1）作为丙型肝炎病毒（HCV）感染期间线粒体抗病毒信号蛋白（MAVS）介导的信号通路的负调节剂。NLRX1 的耗竭增强了 HCV 触发的干扰素（IFN）信号的激活，并导致肝细胞中 HCV 复制的抑制。NLRX1 是一种 HCV 诱导的蛋白，与 MAVS 相互作用，并通过蛋白酶体途径介导 K48 连接的多泛素化和随后的 MAVS 降解。此外，多聚（C）结合蛋白 2（PCBP2）与 NLRX1 相互作用，参与 NLRX1 诱导的 MAVS 降解和 HCV 感染期间抗病毒反应的抑制。诱变分析进一步表明，NLRX1 的 NOD 对于 NLRX1 与 PCBP2 相互作用并随后诱导 MAVS 降解是必不可少的。我们的研究揭示了一种精细调节先天免疫的关键机制，通过该机制，NLRX1 通过募集 PCBP2 到 MAVS 来诱导 MAVS 降解，从而抑制视黄酸诱导基因 I 样受体（RLR）-MAVS 信号级联反应。NLRX1 是先天免疫的负调节剂，是 HCV 建立持续感染的关键宿主因子。先天免疫需要被严格调控，以最大限度地提高抗病毒反应并最小化免疫介导的病理学，但潜在的机制尚不清楚。在这项研究中，我们报告 NLRX1 是 HCV 感染的促病毒宿主因子，并且作为 HCV 触发的先天免疫反应的负调节剂发挥作用。NLRX1 将 PCBP2 募集到 MAVS 并诱导 K48 连接的多泛素化和 MAVS 的降解，导致 IFN 信号通路的负调节并促进 HCV 感染。总的来说，这项研究为病毒感染期间先天免疫如何被调控提供了有趣的见解。
