Wang Yang-Yang, Wang Xue-Li, Li Zhuo-Cong, Zhang Can, Xu Xiao, Cui Bao-Jie, Tian Meng-Ze, Zhou Chu-Jing, Xu Na, Wu Yue, Yang Xiao-Li, Chen Dan-Dan, Lu Long-Feng, Li Shun
Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China.
University of Chinese Academy of Sciences, Beijing, Beijing, China.
J Virol. 2025 Feb 25;99(2):e0158324. doi: 10.1128/jvi.01583-24. Epub 2025 Jan 14.
Although fish possess an effective interferon (IFN) system to defend against viral infection, grass carp reovirus (GCRV) still causes epidemic hemorrhagic disease and tremendous economic loss in grass carp. Therefore, it is necessary to investigate the immune escape strategies employed by GCRV. In this study, we show that the structural protein VP4 of GCRV (encoded by the S6 segment) significantly restricts IFN expression by degrading stimulator of IFN genes (STING) through the autophagy-lysosome-dependent pathway. First, overexpression of VP4 inhibited the expression of IFN induced by GCRV and polyinosinic-polycytidylic acid (poly I:C) at both the promoter and mRNA levels. Second, VP4 was found to associate with STING, and the N-terminal transmembrane domain is essential for this interaction. Additionally, VP4 dramatically blocked STING-induced IFN expression and weakened its antiviral capacity. Further mechanistic studies revealed that VP4 degrades STING via the autophagy-lysosome pathway in a dose-dependent manner. Interestingly, toll-interacting protein (TOLLIP), a selective autophagy receptor, was found to interact with VP4 and reduce VP4-mediated STING degradation after knockdown. Finally, overexpression of VP4 facilitated GCRV proliferation, while its depletion had the opposite effect. These findings indicate that GCRV VP4 recruits TOLLIP to degrade STING and achieve immune escape. This enhances our comprehension of aquatic virus pathogenesis.
Upon virus invasion, fish cells employ a multitude of strategies to defend against infection. Consequently, viruses have evolved a plethora of tactics to evade host antiviral mechanisms. To date, fewer studies have been conducted on the immune evasion mechanism of grass carp reovirus (GCRV). In this study, we demonstrate that VP4 of GCRV-873 inhibits interferon expression by interacting with stimulator of IFN gene and degrading it in an autophagy-lysosome-dependent manner through the manipulation of the selective autophagy receptor toll-interacting protein. The findings of this study contribute to our understanding of the novel evasion mechanisms of GCRV and widen our knowledge of the virus-host interactions in lower vertebrates.
尽管鱼类拥有有效的干扰素（IFN）系统来抵御病毒感染，但草鱼呼肠孤病毒（GCRV）仍会引发草鱼流行性出血病并造成巨大经济损失。因此，有必要研究GCRV采用的免疫逃逸策略。在本研究中，我们发现GCRV的结构蛋白VP4（由S6片段编码）通过自噬 - 溶酶体依赖性途径降解干扰素基因刺激物（STING），从而显著限制IFN表达。首先，VP4的过表达在启动子和mRNA水平上均抑制了由GCRV和聚肌苷酸 - 聚胞苷酸（poly I:C）诱导的IFN表达。其次，发现VP4与STING相互作用，并且N端跨膜结构域对于这种相互作用至关重要。此外，VP4显著阻断STING诱导的IFN表达并削弱其抗病毒能力。进一步的机制研究表明，VP4通过自噬 - 溶酶体途径以剂量依赖性方式降解STING。有趣的是，发现Toll相互作用蛋白（TOLLIP）作为一种选择性自噬受体，在敲低后与VP4相互作用并减少VP4介导的STING降解。最后，VP4的过表达促进了GCRV的增殖，而其缺失则产生相反的效果。这些发现表明GCRV VP4招募TOLLIP来降解STING并实现免疫逃逸。这增强了我们对水生病毒发病机制的理解。
病毒入侵时，鱼类细胞采用多种策略抵御感染。因此，病毒也进化出了大量策略来逃避宿主抗病毒机制。迄今为止，对草鱼呼肠孤病毒（GCRV）免疫逃逸机制的研究较少。在本研究中，我们证明GCRV - 873的VP4通过与IFN基因刺激物相互作用，并通过操纵选择性自噬受体Toll相互作用蛋白以自噬 - 溶酶体依赖性方式将其降解，从而抑制干扰素表达。本研究结果有助于我们理解GCRV的新型逃逸机制，并拓宽我们对低等脊椎动物中病毒 - 宿主相互作用的认识。
