{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:53:53Z","timestamp":1790250833939,"version":"4.1.0"},"reference-count":64,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T00:00:00Z","timestamp":1583193600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["K08AI119142"],"award-info":[{"award-number":["K08AI119142"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI131269"],"award-info":[{"award-number":["R21AI131269"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Zika virus (ZIKV) is an emergent member of the Flaviviridae family which causes severe congenital defects and other major sequelae, but the cellular processes that support ZIKV replication are incompletely understood. Related flaviviruses use the endoplasmic reticulum (ER) as a membranous platform for viral replication and induce ER stress during infection. Our data suggest that ZIKV activates IRE1\u03b1, a component of the cellular response to ER stress. IRE1\u03b1 is an ER-resident transmembrane protein that possesses a cytosolic RNase domain. Upon activation, IRE1\u03b1 initiates nonconventional cytoplasmic splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor, which upregulates ER-related targets. We find that ZIKV infection induces XBP1 mRNA splicing and induction of XBP1 target genes. Small molecule inhibitors of IRE1\u03b1, including those specific for the nuclease function, prevent ZIKV-induced cytotoxicity, as does genetic disruption of IRE1\u03b1. Optimal ZIKV RNA replication requires both IRE1\u03b1 and XBP1. Spliced XBP1 has been described to cause ER expansion and remodeling and we find that ER redistribution during ZIKV infection requires IRE1\u03b1 nuclease activity. Finally, we demonstrate that inducible genetic disruption of IRE1\u03b1 and XBP1 impairs ZIKV replication in a mouse model of infection. Together, our data indicate that the ER stress response component IRE1\u03b1 promotes ZIKV infection via XBP1 and may represent a potential therapeutic target.<\/jats:p>","DOI":"10.3390\/v12030278","type":"journal-article","created":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T13:06:23Z","timestamp":1583240783000},"page":"278","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["IRE1\u03b1 Promotes Zika Virus Infection via XBP1"],"prefix":"10.3390","volume":"12","author":[{"given":"Elena P.","family":"Kolpikova","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana R.","family":"Tronco","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas B.","family":"Den Hartigh","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konner J.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8753-1979","authenticated-orcid":false,"given":"Takao","family":"Iwawaki","sequence":"additional","affiliation":[{"name":"Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0265, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1705-0103","authenticated-orcid":false,"given":"Susan L.","family":"Fink","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e119","DOI":"10.1016\/S1473-3099(16)30010-X","article-title":"Zika virus: History of a newly emerging arbovirus","volume":"16","author":"Wikan","year":"2016","journal-title":"Lancet. 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