Zika virus (ZIKV) belongs to the Flaviviridae family and is related to other viruses that cause human diseases. Unlike other flaviviruses, ZIKV infection can cause congenital neurologic disorders and replicates efficiently in reproductive tissues1–3,. Here, we show that ZIKV envelope (E) protein is K63-linked polyubiquitinated by the E3-ubiquitin ligase TRIM7. Accordingly, ZIKV replicates less efficiently in brain and reproductive tissues of Trim7−/− mice. Ubiquitinated E is present on infectious Zika virions when released from specific cell types and enhances virus attachment and entry into cells. Specifically, K63-linked polyubiquitin chains directly interact with the Tim-1 (HAVCR1) receptor, enhancing virus replication in cells and in vivo in brain tissue. Recombinant ZIKV mutants lacking ubiquitination are attenuated in human cells and in a mouse model, but not in live mosquitoes. Monoclonal antibodies against K63-linked polyubiquitin specifically neutralize ZIKV and reduce viremia in mice. Collectively, the results demonstrate that ubiquitination of ZIKV E is an important determinant of virus entry, tropism and pathogenesis.

中文翻译：

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包膜蛋白泛素化驱动寨卡病毒的进入和发病机制

寨卡病毒（ZIKV）属于黄病毒科，与其他引起人类疾病的病毒有关。与其他黄病毒不同，ZIKV 感染可导致先天性神经系统疾病并在生殖组织中有效复制1-3。在这里，我们显示 ZIKV 包膜 (E) 蛋白是由 E3-泛素连接酶 TRIM7 连接的 K63 多泛素化的。因此，ZIKV 在 Trim7-/- 小鼠的大脑和生殖组织中复制效率较低。当从特定细胞类型释放时，泛素化 E 存在于传染性寨卡病毒粒子上，并增强病毒附着和进入细胞。具体来说，K63 连接的多聚泛素链直接与 Tim-1 (HAVCR1) 受体相互作用，增强病毒在细胞和脑组织体内的复制。缺乏泛素化的重组 ZIKV 突变体在人类细胞和小鼠模型中减弱，但在活蚊子中没有。针对 K63 连接的多聚泛素的单克隆抗体可特异性中和 ZIKV 并减少小鼠的病毒血症。总的来说，结果表明 ZIKV E 的泛素化是病毒进入、向性和发病机制的重要决定因素。