College of Veterinary Medicine, Northwest A&F University, Yangling, China.
Institute for Animal Health, Henan Academy of Agricultural Sciences, Key Laboratory of Animal Immunology of the Ministry of Agriculture, Zhengzhou, China.
J Virol. 2024 Oct 22;98(10):e0081624. doi: 10.1128/jvi.00816-24. Epub 2024 Sep 12.
Viruses employ various evasion strategies to establish prolonged infection, with evasion of innate immunity being particularly crucial. Porcine reproductive and respiratory syndrome virus (PRRSV) is a significant pathogen in swine industry, characterized by reproductive failures in sows and respiratory distress in pigs of all ages, leading to substantial economic losses globally. In this study, we found that the non-structural protein 5 (Nsp5) of PRRSV antagonizes innate immune responses via inhibiting the expression of type I interferon (IFN-I) and IFN-stimulated genes (ISGs), which is achieved by degrading multiple proteins of RIG-I-like receptor (RLR) signaling pathway (RIG-I, MDA5, MAVS, TBK1, IRF3, and IRF7). Furthermore, we showed that PRRSV Nsp5 is located in endoplasmic reticulum (ER), where it promotes accumulation of RLR signaling pathway proteins. Further data demonstrated that Nsp5 activates reticulophagy (ER-phagy), which is responsible for the degradation of RLR signaling pathway proteins and IFN-I production. Mechanistically, Nsp5 interacts with one of the ER-phagy receptor family with sequence similarity 134 member B (FAM134B), promoting the oligomerization of FAM134B. These findings elucidate a novel mechanism by which PRRSV utilizes FAM134B-mediated ER-phagy to elude host antiviral immunity.IMPORTANCEInnate immunity is the first line of host defense against viral infections. Therefore, viruses developed numerous mechanisms to evade the host innate immune responses for their own benefit. PRRSV, one of the most important endemic swine viruses, poses a significant threat to the swine industry worldwide. Here, we demonstrate for the first time that PRRSV utilizes its non-structural protein Nsp5 to degrade multiple proteins of RLR signaling pathways, which play important roles in IFN-I production. Moreover, FAM134B-mediated ER-phagy was further proved to be responsible for the protein's degradation. Our study highlights the critical role of ER-phagy in immune evasion of PRRSV to favor replication and provides new insights into the prevention and control of PRRSV.
病毒采用各种逃避策略来建立长期感染，其中逃避先天免疫尤为关键。猪繁殖与呼吸综合征病毒（PRRSV）是猪业的重要病原体，其特征是母猪繁殖失败和各年龄段猪只呼吸窘迫，导致全球经济损失巨大。在本研究中，我们发现 PRRSV 的非结构蛋白 5（Nsp5）通过降解 RIG-I 样受体（RLR）信号通路的多种蛋白来拮抗先天免疫反应，从而抑制 I 型干扰素（IFN-I）和 IFN 刺激基因（ISGs）的表达，这些蛋白包括 RIG-I、MDA5、MAVS、TBK1、IRF3 和 IRF7。此外，我们表明 PRRSV Nsp5 位于内质网（ER）中，在那里它促进 RLR 信号通路蛋白的积累。进一步的数据表明，Nsp5 激活自噬（ER-phagy），这负责降解 RLR 信号通路蛋白和 IFN-I 的产生。从机制上讲，Nsp5 与 ER-phagy 受体家族的一个成员 134 成员 B（FAM134B）相互作用，促进 FAM134B 的寡聚化。这些发现阐明了 PRRSV 利用 FAM134B 介导的 ER-phagy 逃避宿主抗病毒免疫的新机制。
先天免疫是宿主抵御病毒感染的第一道防线。因此，病毒发展了多种机制来逃避宿主先天免疫反应，以谋取自身利益。PRRSV 是最重要的地方性猪病毒之一，对全球养猪业构成重大威胁。在这里，我们首次证明 PRRSV 利用其非结构蛋白 Nsp5 降解 RLR 信号通路的多种蛋白，这些蛋白在 IFN-I 产生中发挥重要作用。此外，进一步证明 FAM134B 介导的 ER-phagy 负责蛋白的降解。我们的研究强调了 ER-phagy 在 PRRSV 免疫逃避中的关键作用，有利于其复制，并为 PRRSV 的预防和控制提供了新的见解。
