Institutes of Biology and Medical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, 215000, China.
Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, 215000, China.
Adv Sci (Weinh). 2024 Oct;11(39):e2408024. doi: 10.1002/advs.202408024. Epub 2024 Aug 19.
Arboviruses, transmitted by medical arthropods, pose a serious health threat worldwide. During viral infection, Post Translational Modifications (PTMs) are present on both host and viral proteins, regulating multiple processes of the viral lifecycle. In this study, a mammalian E3 ubiquitin ligase WWP2 (WW domain containing E3 ubiquitin ligase 2) is identified, which interacts with the NS1 protein of Zika virus (ZIKV) and mediates K63 and K48 ubiquitination of Lys 265 and Lys 284, respectively. WWP2-mediated NS1 ubiquitination leads to NS1 degradation via the ubiquitin-proteasome pathway, thereby inhibiting ZIKV infection in mammalian hosts. Simultaneously, it is found Su(dx), a protein highly homologous to host WWP2 in mosquitoes, is capable of ubiquitinating NS1 in mosquito cells. Unexpectedly, ubiquitination of NS1 in mosquitoes does not lead to NS1 degradation; instead, it promotes viral infection in mosquitoes. Correspondingly, the NS1 K265R mutant virus is less infectious to mosquitoes than the wild-type (WT) virus. The above results suggest that the ubiquitination of the NS1 protein confers different adaptations of ZIKV to hosts and vectors, and more importantly, this explains why NS1 K265-type strains have become predominantly endemic in nature. This study highlights the potential application in antiviral drug and vaccine development by targeting viral proteins' PTMs.
虫媒传播的虫媒病毒对全球健康构成严重威胁。在病毒感染过程中，宿主和病毒蛋白上都存在翻译后修饰（PTMs），调节病毒生命周期的多个过程。在这项研究中，鉴定了一种哺乳动物 E3 泛素连接酶 WWP2（WW 结构域包含 E3 泛素连接酶 2），它与寨卡病毒（ZIKV）的 NS1 蛋白相互作用，并介导赖氨酸 265 和赖氨酸 284 上的 K63 和 K48 泛素化。WWP2 介导的 NS1 泛素化导致 NS1 通过泛素蛋白酶体途径降解，从而抑制哺乳动物宿主中的 ZIKV 感染。同时，发现蚊子中与宿主 WWP2 高度同源的 Su(dx)蛋白能够在蚊子细胞中泛素化 NS1。出乎意料的是，蚊子中 NS1 的泛素化不会导致 NS1 降解；相反，它促进了蚊子中的病毒感染。相应地，与野生型（WT）病毒相比，NS1 K265R 突变病毒对蚊子的感染性较低。上述结果表明，NS1 蛋白的泛素化赋予 ZIKV 对宿主和载体的不同适应能力，更重要的是，这解释了为什么 NS1 K265 型毒株在自然界中已成为主要地方性毒株。本研究强调了通过靶向病毒蛋白的 PTMs 开发抗病毒药物和疫苗的潜力。
