MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.
J Virol. 2024 May 14;98(5):e0019524. doi: 10.1128/jvi.00195-24. Epub 2024 Apr 24.
The host cytoskeleton plays crucial roles in various stages of virus infection, including viral entry, transport, replication, and release. However, the specific mechanisms by which intermediate filaments are involved in orthoflavivirus infection have not been well understood. In this study, we demonstrate that the Japanese encephalitis virus (JEV) remodels the vimentin network, resulting in the formation of cage-like structures that support viral replication. Mechanistically, JEV NS1 and NS1' proteins induce the translocation of CDK1 from the nucleus to the cytoplasm and interact with it, leading to the phosphorylation of vimentin at Ser56. This phosphorylation event recruits PLK1, which further phosphorylates vimentin at Ser83. Consequently, these phosphorylation modifications convert the typically filamentous vimentin into non-filamentous "particles" or "squiggles." These vimentin "particles" or "squiggles" are then transported retrogradely along microtubules to the endoplasmic reticulum, where they form cage-like structures. Notably, NS1' is more effective than NS1 in triggering the CDK1-PLK1 cascade response. Overall, our study provides new insights into how JEV NS1 and NS1' proteins manipulate the vimentin network to facilitate efficient viral replication.
Japanese encephalitis virus (JEV) is a mosquito-borne orthoflavivirus that causes severe encephalitis in humans, particularly in Asia. Despite the availability of a safe and effective vaccine, JEV infection remains a significant public health threat due to limited vaccination coverage. Understanding the interactions between JEV and host proteins is essential for developing more effective antiviral strategies. In this study, we investigated the role of vimentin, an intermediate filament protein, in JEV replication. Our findings reveal that JEV NS1 and NS1' proteins induce vimentin rearrangement, resulting in the formation of cage-like structures that envelop the viral replication factories (RFs), thus facilitating efficient viral replication. Our research highlights the importance of the interplay between the cytoskeleton and orthoflavivirus, suggesting that targeting vimentin could be a promising approach for the development of antiviral strategies to inhibit JEV propagation.
宿主细胞骨架在病毒感染的各个阶段发挥着关键作用，包括病毒进入、运输、复制和释放。然而，中间丝参与正粘病毒感染的具体机制尚未得到很好的理解。在这项研究中，我们证明日本脑炎病毒（JEV）重塑了波形蛋白网络，形成笼状结构，支持病毒复制。在机制上，JEV NS1 和 NS1'蛋白诱导 CDK1 从核内易位到细胞质，并与之相互作用，导致波形蛋白丝氨酸 56 磷酸化。这种磷酸化事件募集 PLK1，其进一步磷酸化波形蛋白丝氨酸 83。因此，这些磷酸化修饰将典型的丝状波形蛋白转化为非丝状的“颗粒”或“扭结”。这些波形蛋白“颗粒”或“扭结”随后沿微管逆行运输到内质网，在那里它们形成笼状结构。值得注意的是，NS1'比 NS1 更有效地触发 CDK1-PLK1 级联反应。总的来说，我们的研究提供了新的见解，即 JEV NS1 和 NS1'蛋白如何操纵波形蛋白网络促进病毒的有效复制。
日本脑炎病毒（JEV）是一种蚊媒正粘病毒，可导致人类严重脑炎，特别是在亚洲。尽管有安全有效的疫苗，但由于疫苗接种覆盖率有限，JEV 感染仍然是一个重大的公共卫生威胁。了解 JEV 与宿主蛋白之间的相互作用对于开发更有效的抗病毒策略至关重要。在这项研究中，我们研究了中间丝蛋白波形蛋白在 JEV 复制中的作用。我们的研究结果表明，JEV NS1 和 NS1'蛋白诱导波形蛋白重排，导致形成笼状结构，包围病毒复制工厂（RFs），从而促进病毒的有效复制。我们的研究强调了细胞骨架和正粘病毒之间相互作用的重要性，表明靶向波形蛋白可能是开发抑制 JEV 传播的抗病毒策略的有前途的方法。
