Ye Yilu, Sun Tingting, Guo Saisai, Zhao Jianyuan, Li Xiaoyu, Wang Jing, Cen Shan
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100050, China.
Biosaf Health. 2025 Mar 22;7(2):122-131. doi: 10.1016/j.bsheal.2025.03.003. eCollection 2025 Apr.
Rab proteins are involved in all facets of the vesicular transport process and play significant roles in different steps of the viral life cycle. Rab4b is a pivotal player in the endocytic recycling of proteins, whereas its roles in viral replication are still largely unknown. Our earlier work identified Rab4b as a host factor required to replicate the influenza A virus (IAV). Here, we further validated the impact of Rab4b on viral replication by silencing or overexpressing Rab4b. The results showed that silencing Rab4b significantly decreased IAV and influenza B virus (IBV) production. Overexpression of Rab4b enhanced IAV infection. We provided robust evidence to support the important role of Rab4b in facilitating IAV growth independent of the host innate immunity. Mechanism study revealed the involvement of Rab4b in the early steps of the IAV life cycle, including virus attachment, endocytosis of viral particles, virus-host membrane fusion, and nuclear import of viral nucleoprotein NP). Furthermore, we found that Rab4b interacts with viral ribonucleoprotein (RNP) complexes, suggesting that Rab4b binds to RNP complex to facilitate viral replication. In summary, this work provided the first evidence to support the involvement of Rab4b in the IAV replication. Understanding the mechanisms underlying IAV and Rab4b interactions helps elucidate viral infection and pathogenesis and leads to the development of antiviral therapeutics.
Rab蛋白参与囊泡运输过程的各个方面，并在病毒生命周期的不同阶段发挥重要作用。Rab4b是蛋白质内吞再循环中的关键因子，但其在病毒复制中的作用仍不清楚。我们早期的研究确定Rab4b是甲型流感病毒（IAV）复制所需的宿主因子。在此，我们通过沉默或过表达Rab4b进一步验证了Rab4b对病毒复制的影响。结果表明，沉默Rab4b显著降低IAV和乙型流感病毒（IBV）的产生。Rab4b的过表达增强了IAV感染。我们提供了有力证据支持Rab4b在促进IAV生长中发挥重要作用，且不依赖于宿主固有免疫。机制研究揭示Rab4b参与IAV生命周期的早期步骤，包括病毒附着、病毒颗粒的内吞作用、病毒-宿主膜融合以及病毒核蛋白NP的核输入。此外，我们发现Rab4b与病毒核糖核蛋白（RNP）复合物相互作用，这表明Rab4b与RNP复合物结合以促进病毒复制。总之，这项工作提供了首个证据支持Rab4b参与IAV复制。了解IAV与Rab4b相互作用的机制有助于阐明病毒感染和发病机制，并推动抗病毒治疗药物的开发。
