Autophagy- mediated downregulation of AXL and TIM-1 promotes sustained Zika virus infection

• 成果类型: Article
• 署名作者: Yu, Jingyou; Zheng, Yi-Min; Sheridan, Megan A.; Li, Pei; Ezashi, Toshihiko; Roberts, R. Michael; Liu, Shan-Lu
• 署名单位: University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; State Key Laboratory of Respiratory Disease; Guangzhou Medical University; Guangzhou Laboratory; University of Missouri System; University of Missouri Columbia; University of Missouri System; University of Missouri Columbia; University of Missouri System; University of Missouri Columbia; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8967
• DOI: 10.1073/pnas.2427241122
• 发表日期: 2025-05-23
• 关键词: t-cell immunoglobulin; phosphatidylserine receptors; superinfection exclusion; proteins; entry; envelope

摘要

Zika virus (ZIKV) infection can lead to a variety of clinical outcomes, including severe congenital abnormalities. The phosphatidylserine receptors AXL and TIM-1 are recognized as critical entry factors for ZIKV in vitro. However, it remains unclear whether and how ZIKV regulates these receptors during infection. In this study, we investigated AXL and TIM-1 expression in human lung adenocarcinoma epithelial A549 cells, glioblastoma U87 cells, and embryonic stem cell-derived trophoblasts following ZIKV infection. We found that both the Asian strain FSS13025 and the African strain MR766 of ZIKV downregulate AXL, with a milder effect on TIM-1. We identified several ZIKV proteins, notably envelope (E), NS2A, NS3, and NS4B, that contribute to this downregulation. Notably, treatment with lysosomal inhibitor NH4Cl or the autophagy inhibitor 3-methyladenine mitigated the AXL/TIM-1 downregulation, indicating autophagy's involvement in the process. Importantly, this downregulation facilitates sustained viral replication and promotes viral spread by preventing superinfection and limiting cell death, which is also associated with impaired innate immune signaling. Our findings uncover a mechanism by which ZIKV downregulates entry factors to enhance prolonged viral replication and spread.