Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, People's Republic of China.
College of Animal Science and Technology, Jilin Agricultural University, Changchun, People's Republic of China.
J Virol. 2019 Aug 28;93(18). doi: 10.1128/JVI.00322-19. Print 2019 Sep 15.
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. 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.
副粘病毒与宿主细胞建立密切而复杂的相互作用，以抵抗细胞引发的抗病毒反应。在宿主中的各种模式识别受体中，细胞质 RNA 解旋酶与病毒 RNA 相互作用，激活线粒体抗病毒信号蛋白 (MAVS)，随后激活细胞干扰素 (IFN) 反应。另一方面，病毒探索了多种策略来抵抗宿主免疫。在这项研究中，我们发现新城疫病毒 (NDV) 感染诱导 MAVS 降解。进一步分析表明，NDV V 蛋白通过泛素-蛋白酶体途径降解 MAVS，以抑制 IFN-β 的产生。此外，NDV V 蛋白通过赖氨酸 362 和赖氨酸 461 泛素导致 MAVS 的蛋白酶体降解，从而阻止 IFN 的产生。进一步的研究表明，NDV V 蛋白招募 E3 泛素连接酶 RNF5 对 MAVS 进行多泛素化和降解。与野生型 NDV 感染相比，V 缺失型 NDV 诱导的 MAVS 降解减弱，感染后期 IFN-β 的产生增强。其他几种副粘病毒 V 蛋白表现出与 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 蛋白靶向 MAVS 抑制细胞 IFN 产生的新作用，这进一步证实了病毒协调细胞抗病毒反应以适应自身利益。宿主抗 RNA 病毒先天免疫主要依赖于视黄酸诱导基因 I 和黑色素瘤分化相关蛋白 5 的识别，并随后通过与 MAVS 相互作用启动下游信号。另一方面，病毒已经开发出各种策略来对抗 MAVS 介导的信号。副粘病毒调节 MAVS 以利于其感染的机制尚不清楚。在本文中，我们证明 NDV 和其他几种副粘病毒的 V 蛋白通过 E3 泛素连接酶 RING 指蛋白 5 (RNF5) 将 MAVS 靶向泛素介导的降解。MAVS 降解导致下游 IFN-β 途径的抑制，从而有利于病毒增殖。我们的研究揭示了 NDV 逃避宿主先天免疫的新机制，并为控制副粘病毒感染的治疗策略提供了新的见解。
