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Open AccessArticle

Flavivirus Nonstructural Protein NS5 Dysregulates HSP90 to Broadly Inhibit JAK/STAT Signaling

1
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
2
Departments of Global Health and Microbiology, University of Washington, Seattle, WA 98195, USA
3
Division of Pulmonary, Critical Care & Sleep Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA
4
Shorewood High School, Shoreline, WA 98133, USA
*
Authors to whom correspondence should be addressed.
Current address: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga 2678, Australia.
These authors contributed equally.
Cells 2020, 9(4), 899; https://doi.org/10.3390/cells9040899
Received: 29 February 2020 / Revised: 29 March 2020 / Accepted: 1 April 2020 / Published: 7 April 2020
(This article belongs to the Special Issue Zika Virus and Host Interactions)
Pathogenic flaviviruses antagonize host cell Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling downstream of interferons α/β. 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–HSP90 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. View Full-Text
Keywords: flavivirus; JAK/STAT; cytokine; West Nile virus; Zika virus; HSP90; NS5; virus–host interactions; anti-viral signaling; immune response flavivirus; JAK/STAT; cytokine; West Nile virus; Zika virus; HSP90; NS5; virus–host interactions; anti-viral signaling; immune response
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Roby, J.A.; Esser-Nobis, K.; Dewey-Verstelle, E.C.; Fairgrieve, M.R.; Schwerk, J.; Lu, A.Y.; Soveg, F.W.; Hemann, E.A.; Hatfield, L.D.; Keller, B.C.; Shapiro, A.; Forero, A.; Stencel-Baerenwald, J.E.; Savan, R.; Gale, M., Jr. Flavivirus Nonstructural Protein NS5 Dysregulates HSP90 to Broadly Inhibit JAK/STAT Signaling. Cells 2020, 9, 899.

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