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Here, we show that flaviviruses inhibit JAK\/STAT signaling induced by a wide range of cytokines beyond interferon, including interleukins. This broad inhibition was mapped to viral nonstructural protein 5 (NS5) binding to cellular heat shock protein 90 (HSP90), resulting in reduced Janus kinase\u2013HSP90 interaction and thus destabilization of unchaperoned JAKs (and other kinase clients) of HSP90 during infection by Zika virus, West Nile virus, and Japanese encephalitis virus. Our studies implicate viral dysregulation of HSP90 and the JAK\/STAT pathway as a critical determinant of cytokine signaling control during flavivirus infection.<\/jats:p>","DOI":"10.3390\/cells9040899","type":"journal-article","created":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T05:59:47Z","timestamp":1586325587000},"page":"899","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Flavivirus Nonstructural Protein NS5 Dysregulates HSP90 to Broadly Inhibit JAK\/STAT Signaling"],"prefix":"10.3390","volume":"9","author":[{"given":"Justin A.","family":"Roby","sequence":"first","affiliation":[{"name":"Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Esser-Nobis","sequence":"additional","affiliation":[{"name":"Center for Innate Immunity 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy Y.","family":"Lu","sequence":"additional","affiliation":[{"name":"Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA"},{"name":"Departments of Global Health and Microbiology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank W.","family":"Soveg","sequence":"additional","affiliation":[{"name":"Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily A.","family":"Hemann","sequence":"additional","affiliation":[{"name":"Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren D.","family":"Hatfield","sequence":"additional","affiliation":[{"name":"Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C.","family":"Keller","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care & Sleep Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Shorewood High School, Shoreline, WA 98133, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Forero","sequence":"additional","affiliation":[{"name":"Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of 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