Cells
(Apr 2020)
Flavivirus Nonstructural Protein NS5 Dysregulates HSP90 to Broadly Inhibit JAK/STAT Signaling
Justin A. Roby,
Katharina Esser-Nobis,
Elyse C. Dewey-Verstelle,
Marian R. Fairgrieve,
Johannes Schwerk,
Amy Y. Lu,
Frank W. Soveg,
Emily A. Hemann,
Lauren D. Hatfield,
Brian C. Keller,
Alexander Shapiro,
Adriana Forero,
Jennifer E. Stencel-Baerenwald,
Ram Savan,
Michael Gale
Affiliations
Justin A. Roby
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Katharina Esser-Nobis
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Elyse C. Dewey-Verstelle
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Marian R. Fairgrieve
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Johannes Schwerk
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Amy Y. Lu
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Frank W. Soveg
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Emily A. Hemann
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Lauren D. Hatfield
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Brian C. Keller
Division of Pulmonary, Critical Care & Sleep Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA
Alexander Shapiro
Shorewood High School, Shoreline, WA 98133, USA
Adriana Forero
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Jennifer E. Stencel-Baerenwald
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Ram Savan
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
Michael Gale
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA
DOI
https://doi.org/10.3390/cells9040899
Journal volume & issue
Vol. 9,
no. 4
Abstract
Read online
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.
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