Jiang Yanliang, Zhao Yongliang, Deng Jie, Wu Xiaoyan, Li Jian, Guo Dong, Xu Ke, Qin Yali, Chen Mingzhou
State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China.
Cell Biosci. 2025 Apr 21;15(1):50. doi: 10.1186/s13578-025-01384-z.
The cytoskeletal framework plays a critical role in the early stages of human parainfluenza virus type 3 (HPIV3) replication, including viral mRNA synthesis and translation. However, its contribution to later stages of infection, particularly in the context of RNA biology, is not well understood. This study focuses on the role of the cytoskeleton in viral nucleocapsid (vRNP, a ribonucleoprotein complex essential for RNA virus replication) transport, assembly, and budding, and explores the cooperative role of the small GTPase RAB11A and its effector RAB11 family interacting protein 2 (FIP2) in vRNP trafficking. These processes are crucial for respiratory RNA viruses like respiratory syncytial virus (RSV) and influenza A virus (IAV), highlighting the importance of RNA-protein interactions in viral pathogenesis.
Through the use of cytoskeleton-depolymerizing agents, the study identified actin microfilaments as indispensable for vRNP transport, viral assembly, and viral particle budding. It also revealed the importance of the RAB11A-FIP2 complex in these processes, which are critical for the intracellular trafficking of viral RNA. The development of peptides targeting the RAB11A-FIP2 complex led to the suppression of RAB11A function in infected cells, resulting in vRNP aggregation in the cytoplasm and reduced viral replication. The peptide YT-DRI showed strong broad-spectrum antiviral activity against HPIV3, RSV, and IAV in cellular and animal models and was effective against co-infections in vitro. The antiviral effects of YT-DRI were abolished upon deletion of RAB11A or core components of the RAB11A pathway.
This work introduces a promising broad-spectrum antiviral strategy for respiratory tract infections by targeting the RAB11A-FIP2 complex, which regulates the transport and assembly of viral RNA. By disrupting this pathway, YT-DRI effectively inhibits the replication of multiple respiratory RNA viruses, including HPIV3, RSV, and IAV.
细胞骨架框架在人副流感病毒3型（HPIV3）复制的早期阶段发挥着关键作用，包括病毒mRNA的合成和翻译。然而，其在感染后期的作用，特别是在RNA生物学背景下，尚未得到充分了解。本研究聚焦于细胞骨架在病毒核衣壳（vRNP，一种RNA病毒复制所必需的核糖核蛋白复合物）运输、组装和出芽中的作用，并探讨小GTP酶RAB11A及其效应器RAB11家族相互作用蛋白2（FIP2）在vRNP运输中的协同作用。这些过程对于呼吸道合胞病毒（RSV）和甲型流感病毒（IAV）等呼吸道RNA病毒至关重要，凸显了RNA-蛋白质相互作用在病毒发病机制中的重要性。
通过使用细胞骨架解聚剂，该研究确定肌动蛋白微丝对于vRNP运输、病毒组装和病毒粒子出芽是不可或缺的。它还揭示了RAB11A-FIP2复合物在这些过程中的重要性，这些过程对于病毒RNA的细胞内运输至关重要。靶向RAB11A-FIP2复合物的肽的开发导致感染细胞中RAB11A功能的抑制，导致vRNP在细胞质中聚集并减少病毒复制。肽YT-DRI在细胞和动物模型中对HPIV3、RSV和IAV表现出强大的广谱抗病毒活性，并且在体外对共感染有效。当删除RAB11A或RAB11A途径的核心成分时,YT-DRI的抗病毒作用被消除。
这项工作通过靶向RAB11A-FIP2复合物引入了一种有前景的呼吸道感染广谱抗病毒策略，该复合物调节病毒RNA的运输和组装。通过破坏这一途径，YT-DRI有效地抑制了多种呼吸道RNA病毒的复制，包括HPIV3、RSV和IAV。
