Newcastle Disease Virus V Protein Degrades Mitochondrial Antiviral Signaling Protein To Inhibit Host Type I Interferon Production via E3 Ubiquitin Ligase RNF5
Newcastle Disease Virus V Protein Degrades Mitochondrial Antiviral Signaling Protein To Inhibit Host Type I Interferon Production via E3 Ubiquitin Ligase RNF5
复制标题
新城疫病毒 V 蛋白降解线粒体抗病毒信号蛋白，通过 E3 泛素连接酶 RNF5 抑制宿主 I 型干扰素产生
DOI：
10.1128/jvi.00322-19
复制
发表时间：
2019-09-01
影响因子：
5.4
通讯作者：
Ding, Chan
中科院分区：
文献类型：
--
作者：
Sun, Yingjie;Zheng, Hang;Ding, Chan
宿主抗RNA病毒的先天免疫主要依赖于视黄酸诱导基因I和黑色素瘤分化相关蛋白5的识别，随后通过与MAVS的相互作用启动下游信号传导。另一方面，病毒已经开发了各种策略来抵消MAVS介导的信号传导。副粘病毒调节MAVS以利于其感染的机制仍不清楚。在这篇文章中，我们证明了NDV和其他几种副粘病毒的V蛋白靶向MAVS，通过E3泛素连接酶环指蛋白5（RNF 5）进行泛素介导的降解。MAVS降解导致下游IFN-β途径的抑制，因此有利于病毒增殖。我们的研究揭示了NDV逃避宿主天然免疫的新机制，并为控制副粘病毒感染的治疗策略提供了新的见解。副粘病毒与宿主细胞建立密切而复杂的相互作用，以抵消由细胞引起的抗病毒反应。在宿主中的各种模式识别受体中，胞质RNA解旋酶与病毒RNA相互作用以激活线粒体抗病毒信号蛋白（MAVS）和随后的细胞干扰素（IFN）应答。另一方面，病毒探索多种策略来抵抗宿主免疫。在本研究中，我们发现纽卡斯尔病病毒（NDV）感染诱导MAVS降解。进一步分析表明，NDV蛋白通过遍在蛋白-蛋白酶体途径降解MAVS，抑制IFN-β的产生。此外，NDV V蛋白导致蛋白酶体通过Lys 362和Lys 461泛素降解MAVS，以阻止IFN的产生。进一步的研究表明，NDV V蛋白募集E3泛素连接酶RNF 5来聚泛素化和降解MAVS。与野生型NDV感染水平相比，V缺陷型NDV诱导MAVS降解减弱，并在感染后期诱导IFN-β产生增加。其他几种副粘病毒V蛋白具有与NDV V蛋白相似的降解MAVS和阻断IFN产生的活性。本研究揭示了NDV V蛋白在靶向MAVS以抑制细胞IFN产生中的新作用，这加强了病毒协调细胞抗病毒应答以使其自身受益的事实。重要性宿主抗RNA病毒先天免疫主要依赖于视黄酸诱导基因I和黑素瘤分化相关蛋白5的识别，随后通过与MAVS的相互作用启动下游信号传导。另一方面，病毒已经开发了各种策略来抵消MAVS介导的信号传导。副粘病毒调节MAVS以利于其感染的机制仍不清楚。在这篇文章中，我们证明了NDV和其他几种副粘病毒的V蛋白靶向MAVS，通过E3泛素连接酶环指蛋白5（RNF 5）进行泛素介导的降解。MAVS降解导致下游IFN-β途径的抑制，因此有利于病毒增殖。我们的研究揭示了NDV逃避宿主天然免疫的新机制，并为控制副粘病毒感染的治疗策略提供了新的见解。
Host anti-RNA virus innate immunity relies mainly on the recognition by retinoic acid-inducible gene I and melanoma differentiation-associated protein 5 and subsequently initiates downstream signaling through interaction with MAVS. On the other hand, viruses have developed various strategies to counteract MAVS-mediated signaling. The mechanism for paramyxoviruses regulating MAVS to benefit their infection remains unknown. In this article, we demonstrate that the V proteins of NDV and several other paramyxoviruses target MAVS for ubiquitin-mediated degradation through E3 ubiquitin ligase RING-finger protein 5 (RNF5). MAVS degradation leads to the inhibition of the downstream IFN-β pathway and therefore benefits virus proliferation. Our study reveals a novel mechanism of NDV evading host innate immunity and provides insight into the therapeutic strategies for the control of paramyxovirus infection. ABSTRACT Paramyxovirus establishes an intimate and complex interaction with the host cell to counteract the antiviral responses elicited by the cell. Of the various pattern recognition receptors in the host, the cytosolic RNA helicases interact with viral RNA to activate the mitochondrial antiviral signaling protein (MAVS) and subsequent cellular interferon (IFN) response. On the other hand, viruses explore multiple strategies to resist host immunity. In this study, we found that Newcastle disease virus (NDV) infection induced MAVS degradation. Further analysis showed that NDV V protein degraded MAVS through the ubiquitin-proteasome pathway to inhibit IFN-β production. Moreover, NDV V protein led to proteasomal degradation of MAVS through Lys362 and Lys461 ubiquitin to prevent IFN production. Further studies showed that NDV V protein recruited E3 ubiquitin ligase RNF5 to polyubiquitinate and degrade MAVS. Compared with levels for wild-type NDV infection, V-deficient NDV induced attenuated MAVS degradation and enhanced IFN-β production at the late stage of infection. Several other paramyxovirus V proteins showed activities of degrading MAVS and blocking IFN production similar to those of NDV V protein. The present study revealed a novel role of NDV V protein in targeting MAVS to inhibit cellular IFN production, which reinforces the fact that the virus orchestrates the cellular antiviral response to its own benefit. IMPORTANCE Host anti-RNA virus innate immunity relies mainly on the recognition by retinoic acid-inducible gene I and melanoma differentiation-associated protein 5 and subsequently initiates downstream signaling through interaction with MAVS. On the other hand, viruses have developed various strategies to counteract MAVS-mediated signaling. The mechanism for paramyxoviruses regulating MAVS to benefit their infection remains unknown. In this article, we demonstrate that the V proteins of NDV and several other paramyxoviruses target MAVS for ubiquitin-mediated degradation through E3 ubiquitin ligase RING-finger protein 5 (RNF5). MAVS degradation leads to the inhibition of the downstream IFN-β pathway and therefore benefits virus proliferation. Our study reveals a novel mechanism of NDV evading host innate immunity and provides insight into the therapeutic strategies for the control of paramyxovirus infection.