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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 ?/?. 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.

SUBMITTER: Roby JA

PROVIDER: S-EPMC7226784 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Roby Justin A JA Esser-Nobis Katharina K Dewey-Verstelle Elyse C EC Fairgrieve Marian R MR Schwerk Johannes J Lu Amy Y AY Soveg Frank W FW Hemann Emily A EA Hatfield Lauren D LD Keller Brian C BC Shapiro Alexander A Forero Adriana A Stencel-Baerenwald Jennifer E JE Savan Ram R Gale Michael M

Cells 20200407 4

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 ...[more]

PMID: 32272626

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Project description:Background & aimsFunctional cure is achieved by a limited number of patients with chronic hepatitis B (CHB) after nucleotide analogue(s) and interferon treatment. It is urgent to develop therapies that can help a larger proportion of patients achieve functional cure. The present study was designed to explore the anti-hepatitis B virus (HBV) potency of interleukin-6 family cytokines and to characterize the underlying mechanisms of the cytokine displaying the highest anti-HBV potency.MethodsHBV-infected cells were used to screened the anti-HBV potency of interleukin-6 family cytokines. The concentration of oncostatin M (OSM) in patients with chronic HBV infection was examined by enzyme-linked immunosorbent assay. The underlying mechanism of OSM anti-HBV was explored through RNA-seq. C57BL/6 mice injected with rAAV8-1.3HBV were used to explore the suppression effect of OSM on HBV in vivo.ResultsOSM is the most effective of the interleukin-6 family cytokines for suppression of HBV replication (percentage of average inhibition: hepatitis B surface antigen, 34.44%; hepatitis B e antigen, 32.52%; HBV DNA, 61.57%). Hepatitis B e antigen-positive CHB patients with high OSM levels had lower hepatitis B surface antigen and hepatitis B e antigen than those with low levels. OSM activated JAK-STAT signaling pathway promoting the formation of STAT1-IRF9 transcription factor complex. Following this, OSM increased the expression of various genes with known functions in innate and adaptive immunity, which was higher expression in patients with CHB in immune clearance phase than in immune tolerance phase (data from GEO: GSE65359). Interferon-induced transmembrane protein 1, one of the most differentially expressed genes, was identified as an HBV restriction factor involved in OSM-mediated anti-HBV effect. In vivo, we also found OSM significantly inhibited HBV replication and induced expression of antiviral effector interferon-induced transmembrane protein 1.ConclusionsOur study shows that OSM remodels the immune response against HBV and exerts potent anti-HBV activity, supporting its further development as a potential therapy for treating CHB.

Dataset Information

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

Publications

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

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