Institute of Pathogen Biology and Immunology of the College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, China.
The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
J Virol. 2018 Jun 29;92(14). doi: 10.1128/JVI.00321-18. Print 2018 Jul 15.
Human innate immunity responds to viral infection by activating the production of interferons (IFNs) and proinflammatory cytokines. The mitochondrial adaptor molecule MAVS plays a critical role in innate immune response to viral infection. In this study, we show that TRIM21 (tripartite motif-containing protein 21) interacts with MAVS to positively regulate innate immunity. Under viral infection, TRIM21 is upregulated through the IFN/JAK/STAT signaling pathway. Knockdown of TRIM21 dramatically impairs innate immune response to viral infection. Moreover, TRIM21 interacts with MAVS and catalyzes its K27-linked polyubiquitination, thereby promoting the recruitment of TBK1 to MAVS. Specifically, the PRY-SPRY domain of TRIM21 is the key domain for its interaction with MAVS, while the RING domain of TRIM21 facilitates the polyubiquitination chains of MAVS. In addition, the MAVS-mediated innate immune response is enhanced by both the PRY-SPRY and RING domains of TRIM21. Mutation analyses of all the lysine residues of MAVS further revealed that Lys325 of MAVS is catalyzed by TRIM21 for the K27-linked polyubiquitination. Overall, this study reveals a novel mechanism by which TRIM21 promotes the K27-linked polyubiquitination of MAVS to positively regulate innate immune response, thereby inhibiting viral infection. Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. MAVS plays a critical role in innate immune response to RNA viral infection. In this study, we demonstrated that TRIM21 targets MAVS to positively regulate innate immunity. Notably, TRIM21 targets and catalyzes K27-linked polyubiquitination of MAVS and then promotes the recruitment of TBK1 to MAVS, leading to upregulation of innate immunity. Our study outlines a novel mechanism by which the IFN signaling pathway blocks RNA virus to escape immune elimination.
天然免疫系统通过激活干扰素（IFN）和促炎细胞因子的产生来响应病毒感染。线粒体衔接分子 MAVS 在抗病毒感染的固有免疫反应中起着关键作用。在这项研究中，我们表明 TRIM21（三结构域包含蛋白 21）与 MAVS 相互作用，正向调节先天免疫。在病毒感染下，TRIM21 通过 IFN/JAK/STAT 信号通路上调。TRIM21 的敲低显著损害了病毒感染的先天免疫反应。此外，TRIM21 与 MAVS 相互作用并催化其 K27 连接的多泛素化，从而促进 TBK1 募集到 MAVS。具体而言，TRIM21 的 PRY-SPRY 结构域是其与 MAVS 相互作用的关键结构域，而 TRIM21 的 RING 结构域促进 MAVS 的多泛素化链。此外，TRIM21 的 PRY-SPRY 和 RING 结构域增强了 MAVS 介导的先天免疫反应。MAVS 的所有赖氨酸残基的突变分析进一步表明，MAVS 的赖氨酸 325 由 TRIM21 催化进行 K27 连接的多泛素化。总体而言，这项研究揭示了 TRIM21 促进 MAVS 的 K27 连接的多泛素化以正向调节先天免疫反应，从而抑制病毒感染的新机制。激活先天免疫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。MAVS 在抗病毒 RNA 感染的固有免疫反应中起着关键作用。在这项研究中，我们证明了 TRIM21 靶向 MAVS 以正向调节先天免疫。值得注意的是，TRIM21 靶向并催化 MAVS 的 K27 连接的多泛素化，然后促进 TBK1 募集到 MAVS，导致先天免疫的上调。我们的研究概述了 IFN 信号通路阻止 RNA 病毒逃避免疫消除的新机制。
