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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。

Envelope protein ubiquitination drives entry and pathogenesis of Zika virus.

机构信息

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.

Centro de Investigaciones Biomédicas, Universidad del Quindío, Armenia, Colombia.

出版信息

Nature. 2020 Sep;585(7825):414-419. doi: 10.1038/s41586-020-2457-8. Epub 2020 Jul 8.

DOI:10.1038/s41586-020-2457-8
PMID:32641828
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7501154/
Abstract

Zika virus (ZIKV) belongs to the family Flaviviridae, and is related to other viruses that cause human diseases. Unlike other flaviviruses, ZIKV infection can cause congenital neurological disorders and replicates efficiently in reproductive tissues. Here we show that the envelope protein (E) of ZIKV is polyubiquitinated by the E3 ubiquitin ligase TRIM7 through Lys63 (K63)-linked polyubiquitination. Accordingly, ZIKV replicates less efficiently in the brain and reproductive tissues of Trim7 mice. Ubiquitinated E is present on infectious virions of ZIKV when they are released from specific cell types, and enhances virus attachment and entry into cells. Specifically, K63-linked polyubiquitin chains directly interact with the TIM1 (also known as HAVCR1) receptor of host cells, which enhances virus entry in cells as well as in brain tissue in vivo. Recombinant ZIKV mutants that lack ubiquitination are attenuated in human cells and in wild-type mice, but not in live mosquitoes. Monoclonal antibodies against K63-linked polyubiquitin specifically neutralize ZIKV and reduce viraemia in mice. Our results demonstrate that the ubiquitination of ZIKV E is an important determinant of virus entry, tropism and pathogenesis.

摘要

Zika 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发育障碍，并在生殖组织中高效复制。在这里，我们表明 ZIKV 的包膜蛋白（E）通过 E3 泛素连接酶 TRIM7 通过赖氨酸 63（K63）连接的多泛素化被多泛素化。相应地，ZIKV 在 Trim7 小鼠的大脑和生殖组织中的复制效率较低。当从特定细胞类型释放时，带有泛素的 ZIKV 包膜蛋白存在于感染性病毒粒子上，并增强病毒的附着和进入细胞。具体而言，K63 连接的多泛素链直接与宿主细胞的 TIM1（也称为 HAVCR1）受体相互作用，这增强了细胞内以及体内脑组织中的病毒进入。缺乏泛素化的重组 ZIKV 突变体在人细胞和野生型小鼠中减弱，但在活蚊子中不减弱。针对 K63 连接的多泛素的单克隆抗体特异性中和 ZIKV 并减少小鼠中的病毒血症。我们的结果表明，ZIKV E 的泛素化是病毒进入、嗜性和发病机制的重要决定因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2190/7501154/63d773a30234/nihms-1588560-f0005.jpg
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