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

doi:10.3390/cells9040899

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

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

Abstract

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.

Original language	English (US)
Article number	899
Journal	Cells
Volume	9
Issue number	4
DOIs	https://doi.org/10.3390/cells9040899
State	Published - Apr 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Anti-viral signaling
Cytokine
Flavivirus
HSP90
Immune response
JAK/STAT
NS5
Virus-host interactions
West nile virus
Zika virus

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cells9040899

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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. (2020). Flavivirus nonstructural protein NS5 dysregulates HSP90 to broadly inhibit JAK/STAT signaling. Cells, 9(4), Article 899. https://doi.org/10.3390/cells9040899

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abstract = "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.",

keywords = "Anti-viral signaling, Cytokine, Flavivirus, HSP90, Immune response, JAK/STAT, NS5, Virus-host interactions, West nile virus, Zika virus",

author = "Roby, {Justin A.} and Katharina Esser-Nobis and Dewey-Verstelle, {Elyse C.} and Fairgrieve, {Marian R.} and Johannes Schwerk and Lu, {Amy Y.} and Soveg, {Frank W.} and Hemann, {Emily A.} and Hatfield, {Lauren D.} and Keller, {Brian C.} and Alexander Shapiro and Adriana Forero and Stencel-Baerenwald, {Jennifer E.} and Ram Savan and Michael Gale",

note = "Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = apr,

doi = "10.3390/cells9040899",

language = "English (US)",

volume = "9",

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AU - Roby, Justin A.

AU - Esser-Nobis, Katharina

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AU - Fairgrieve, Marian R.

AU - Schwerk, Johannes

AU - Lu, Amy Y.

AU - Soveg, Frank W.

AU - Hemann, Emily A.

AU - Hatfield, Lauren D.

AU - Keller, Brian C.

AU - Shapiro, Alexander

AU - Forero, Adriana

AU - Stencel-Baerenwald, Jennifer E.

AU - Savan, Ram

AU - Gale, Michael

PY - 2020/4

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N2 - 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.

AB - 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.

KW - Anti-viral signaling

KW - Cytokine

KW - Flavivirus

KW - HSP90

KW - Immune response

KW - JAK/STAT

KW - NS5

KW - Virus-host interactions

KW - West nile virus

KW - Zika virus

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Flavivirus nonstructural protein NS5 dysregulates HSP90 to broadly inhibit JAK/STAT signaling

Abstract

Bibliographical note

Keywords

UN SDGs

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