Tankyrases inhibit innate antiviral response by PARylating VISA/MAVS and priming it for RNF146-mediated ubiquitination and degradation.
Tankyrases inhibit innate antiviral response by PARylating VISA/MAVS and priming it for RNF146-mediated ubiquitination and degradation.
复制标题
端锚聚合酶通过 PARylating VISA/MAVS 并引发 RNF146 介导的泛素化和降解来抑制先天抗病毒反应
DOI：
10.1073/pnas.2122805119
复制
发表时间：
2022-06-28
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
病毒诱导信号转导蛋白(VISA)/线粒体抗病毒信号转导蛋白(MAVS)是RNA病毒先天免疫应答中必不可少的转接蛋白，了解VISA是如何调控的对于感染性疾病的治疗具有重要意义。在本研究中，我们发现Tankyrase1(TNKS1)和TNKS2通过催化VISA的多(ADP-核糖基)聚合(PAR化)负向调节先天抗病毒反应。VISA的这种修饰是E3泛素连接酶环状蛋白146(RNF146)的信号，它使VISA泛素化并导致其降解。我们的发现揭示了一种通过TNKS-RNF146轴减弱对RNA病毒的先天免疫反应的机制，这可能有助于开发抗RNA病毒感染的药物或疫苗。在病毒感染过程中，维甲酸诱导的类基因受体(RLRs)感应病毒RNA，启动抗病毒先天免疫反应，这种免疫反应是由线粒体适配器蛋白VISA(病毒诱导信号适配器；也称为线粒体抗病毒信号蛋白[MAVS])介导的。VISA受多种翻译后修饰(PTM)的调节，如多泛素化、磷酸化、O-连接的β-d-N-乙酰氨基葡萄糖基化(O-GlcN酰化)和单甲基化。然而，其他形式的PTM是否调节VISA介导的先天性免疫信号仍然难以捉摸。在这里，我们报告了聚(ADP-核糖基化)作用(PARylation)是VISA的一种PTM，它减弱了对RNA病毒的先天免疫反应。通过生化纯化的方法，我们鉴定了Tankyrase 1(TNKS1)是一种VISA相关蛋白。病毒感染导致TNKS1及其同系物TNKS2从胞浆移位到线粒体，并与VISA相互作用。TNKS1和TNKS2催化VISA在Glu137残基上的PAR化，从而为E3连接酶环状蛋白146(RNF146)与K48连接的多泛素化和随后的降解做准备。一致地，TNKS1、TNKS2或RNF146缺乏增加了RNA病毒触发的下游效应基因的诱导，并损害了病毒的复制。此外，TNKS1或TNKS2缺陷小鼠在病毒感染后产生更高水平的I型干扰素(IFN)和促炎细胞因子，并显著降低大脑和肺部的病毒载量。总之，我们的发现揭示了VISA的PAR化在病毒触发的先天性免疫信号中的重要作用，这代表了一种避免过度有害免疫反应的机制。
Virus-induced signal adaptor (VISA)/mitochondrial antiviral signaling protein (MAVS) is an essential adaptor protein in innate immune response to RNA viruses; understanding how VISA is regulated is important for the treatment of infectious diseases. In this study, we discovered that tankyrase 1 (TNKS1) and TNKS2 negatively regulate innate antiviral response by catalyzing Poly(ADP-ribosyl)ation (PARylation) of VISA. This modification of VISA serves as a signal for the E3 ubiquitin ligase Ring figure protein 146 (RNF146), which polyubiquitinates VISA and leads to its degradation. Our findings reveal a mechanism for attenuating innate immune response to RNA viruses by the TNKS–RNF146 axis, which could help the development of drugs or vaccines against RNA virus infection. During viral infection, sensing of viral RNA by retinoic acid–inducible gene-I–like receptors (RLRs) initiates an antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA (virus-induced signal adaptor; also known as mitochondrial antiviral signaling protein [MAVS]). VISA is regulated by various posttranslational modifications (PTMs), such as polyubiquitination, phosphorylation, O-linked β-d-N-acetylglucosaminylation (O-GlcNAcylation), and monomethylation. However, whether other forms of PTMs regulate VISA-mediated innate immune signaling remains elusive. Here, we report that Poly(ADP-ribosyl)ation (PARylation) is a PTM of VISA, which attenuates innate immune response to RNA viruses. Using a biochemical purification approach, we identified tankyrase 1 (TNKS1) as a VISA-associated protein. Viral infection led to the induction of TNKS1 and its homolog TNKS2, which translocated from cytosol to mitochondria and interacted with VISA. TNKS1 and TNKS2 catalyze the PARylation of VISA at Glu137 residue, thereby priming it for K48-linked polyubiquitination by the E3 ligase Ring figure protein 146 (RNF146) and subsequent degradation. Consistently, TNKS1, TNKS2, or RNF146 deficiency increased the RNA virus–triggered induction of downstream effector genes and impaired the replication of the virus. Moreover, TNKS1- or TNKS2-deficient mice produced higher levels of type I interferons (IFNs) and proinflammatory cytokines after virus infection and markedly reduced virus loads in the brains and lungs. Together, our findings uncover an essential role of PARylation of VISA in virus-triggered innate immune signaling, which represents a mechanism to avoid excessive harmful immune response.
登录
查看更多内容
影响因子：
64.8
作者：
Meylan, E;Curran, J;Tschopp, R
通讯作者：
Tschopp, R
影响因子：
10.5
作者：
Chang, W;Dynek, JN;Smith, S
通讯作者：
Smith, S
影响因子：
30.5
作者：
Kawai, T;Takahashi, K;Akira, S
通讯作者：
Akira, S
影响因子：
5.4
作者：
Castanier C;Zemirli N;Portier A;Garcin D;Bidère N;Vazquez A;Arnoult D
通讯作者：
Arnoult D
ADP-核糖基转移酶 PARP11 通过单 ADP 核糖基化泛素 E3 连接酶 β-TrCP 调节干扰素抗病毒反应
影响因子：
28.3
作者：
Guo, Tingting;Zuo, Yibo;Zheng, Hui
通讯作者：
Zheng, Hui