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However, the mechanism responsible for how EV71 breaks through the blood\u2010brain barrier to infect brain cells has yet to be elucidated. By performing a high\u2010throughput small interfering RNA (siRNA) screening and validation, we found that the infection of human brain microvascular endothelial cells (HBMECs) by EV71 was independent of the endocytosis pathways mediated by caveolin, clathrin, and macropinocytosis but dependent on ADP\u2010ribosylation factor 6 (ARF6), a small guanosinetriphosphate (GTP)\u2010binding protein of the Ras superfamily. The specific siRNA targeting ARF6 markedly inhibited HBMECs susceptibility to EV71. EV71 infectivity was inhibited by NAV\u20102729, a specific inhibitor of ARF6, in a dose\u2010dependent manner. The subcellular analysis demonstrated the co\u2010localization of the endocytosed EV71 and ARF6, while knockdown of ARF6 with siRNA remarkably influenced EV71 endocytosis. By immunoprecipitation assays, we found a direct interaction of ARF6 with EV71 viral protein. Furthermore, ARF1, another small GTP\u2010binding protein, was also found to participate in ARF6\u2010mediated EV71 endocytosis. Murine experiments demonstrated that NAV\u20102729 significantly alleviated mortality caused by EV71 infection. Our study revealed a new pathway by which EV71 enters the HBMECs and provides new targets for drug development.<\/jats:p>","DOI":"10.1002\/jmv.28915","type":"journal-article","created":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T09:54:24Z","timestamp":1688723664000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Enterovirus 71 enters human brain microvascular endothelial cells through an ARF6\u2010mediated endocytic pathway"],"prefix":"10.1002","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1529-6807","authenticated-orcid":false,"given":"Yongzhe","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Microbiology, Faculty of Naval Medicine Naval Medical University  Shanghai 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