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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
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Flavivirus Nonstructural Protein NS5 Dysregulates HSP90 to Broadly Inhibit JAK/STAT Signaling

Justin A Roby1, Katharina Esser-Nobis1, Elyse C Dewey-Verstelle1

  • 1Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.

Cells
|April 11, 2020
PubMed

Insights

Flaviviruses broadly inhibit host Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by targeting heat shock protein 90 (HSP90). This viral protein 5 (NS5) interaction destabilizes JAKs, impacting cytokine responses.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Pathogenic flaviviruses, including Zika virus, West Nile virus, and Japanese encephalitis virus, are known to interfere with host cell Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways.
  • This interference is typically observed downstream of interferon-alpha/beta signaling, a critical component of the innate immune response.

Purpose of the Study:

  • To investigate the broad impact of flavivirus infection on cytokine-induced JAK/STAT signaling beyond interferons.
  • To elucidate the molecular mechanisms by which flaviviruses antagonize JAK/STAT signaling.

Main Methods:

  • Utilized cell-based assays to assess JAK/STAT pathway activation in response to various cytokines (interferons and interleukins) during flavivirus infection.
  • Employed co-immunoprecipitation and Western blotting to analyze the interaction between viral nonstructural protein 5 (NS5), Janus kinases (JAKs), and heat shock protein 90 (HSP90).
  • Investigated the effect of NS5-HSP90 interaction on JAK stability and function.

Main Results:

  • Flaviviruses were found to inhibit JAK/STAT signaling induced by a diverse range of cytokines, not limited to interferons.
  • The viral nonstructural protein 5 (NS5) was identified as the key viral factor responsible for this broad inhibition.
  • NS5 binds to cellular heat shock protein 90 (HSP90), disrupting the interaction between HSP90 and Janus kinases (JAKs).
  • This disruption leads to the destabilization of unchaperoned JAKs and other HSP90 client kinases during infection.

Conclusions:

  • Flavivirus infection broadly dysregulates host cytokine signaling by targeting the JAK/STAT pathway.
  • The interaction between viral NS5 and host HSP90 is crucial for antagonizing JAK/STAT signaling and represents a significant viral immune evasion strategy.
  • Understanding this mechanism provides insights into flavivirus pathogenesis and potential therapeutic targets.
Keywords:
HSP90JAK/STATNS5West Nile virusZika virusanti-viral signalingcytokineflavivirusimmune responsevirus–host interactions

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