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

Justin 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 Jr

doi:10.3390/cells9040899

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

Justin 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 Jr

Dentistry and Medical Sciences

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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.

Original language	English
Article number	899
Number of pages	20
Journal	Cells
Volume	9
Issue number	4
DOIs	https://doi.org/10.3390/cells9040899
Publication status	Published - 07 Apr 2020

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10.3390/cells9040899

44020198 published articleFinal published version, 33.8 MBLicence: CC BY

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Roby, J., 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 Jr, 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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title = "Flavivirus nonstructural protein NS5 Dysregulates HSP90 to broadly inhibit JAK/STAT signaling",

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 = "flavivirus, JAK/STAT, cytokine, West Nile virus, Zika virus, HSP90, NS5, virus-host interactions, anti-viral signaling, immune response",

author = "Justin Roby 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 {Gale Jr}, Michael",

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doi = "10.3390/cells9040899",

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AU - Roby, Justin

AU - Esser-Nobis, Katharina

AU - Dewey-Verstelle, Elyse C

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 Jr, Michael

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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 - flavivirus

KW - JAK/STAT

KW - cytokine

KW - West Nile virus

KW - Zika virus

KW - HSP90

KW - NS5

KW - virus-host interactions

KW - anti-viral signaling

KW - immune response

UR - https://www.mdpi.com/2073-4409/9/4/899

U2 - 10.3390/cells9040899

DO - 10.3390/cells9040899

M3 - Article

C2 - 32272626

SN - 2073-4409

VL - 9

JO - Cells

JF - Cells

IS - 4

M1 - 899

ER -

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

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