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Cited by 27interferon and immune responsesMosquito-borne diseases and controlCytokine Signaling Pathways and Interactions

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Tick‐borne flavivirus NS5 antagonizes interferon signaling by inhibiting the catalytic activity of TYK2

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Gracias, Ségolène, Chazal, Maxime, Decombe, Alice, Unterfinger, Yves, Sogues, Adrià, Pruvost, Lauryne, Robert, Valentine, Lacour, Sandrine A, Lemasson, Manon, Sourisseau, Marion, Li, Zhi, Richardson, Jennifer, Pellegrini, Sandra, Decroly, Etienne, Caval, Vincent, Jouvenet, Nolwenn·2023·The EMBO Reports
DOI 10.15252/embr.202357424PMC PMC10702846

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Abstract

The mechanisms utilized by different flaviviruses to evade antiviral functions of interferons are varied and incompletely understood. Using virological approaches, biochemical assays, and mass spectrometry analyses, we report here that the NS5 protein of tick-borne encephalitis virus (TBEV) and Louping Ill virus (LIV), two related tick-borne flaviviruses, antagonize JAK-STAT signaling through interactions with the tyrosine kinase 2 (TYK2). Co-immunoprecipitation (co-IP) experiments, yeast gap-repair assays, computational protein-protein docking and functional studies identify a stretch of 10 residues of the RNA dependent RNA polymerase domain of tick-borne flavivirus NS5, but not mosquito-borne NS5, that is critical for interactions with the TYK2 kinase domain. Additional co-IP assays performed with several TYK2 orthologs reveal that the interaction is conserved across mammalian species. In vitro kinase assays show that TBEV and LIV NS5 reduce the catalytic activity of TYK2. Our results thus illustrate a novel mechanism by which viruses suppress the interferon response.

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Metadata

Authors
Gracias, S., Chazal, M., Decombe, A., Unterfinger, Y., Sogues, A., Pruvost, L., Robert, V., Lacour, S. A., Lemasson, M., Sourisseau, M., Li, Z., Richardson, J., Pellegrini, S., Decroly, E., Caval, V., & Jouvenet, N.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • École Nationale Vétérinaire d'Alfort (FR)
  • VIB-VUB Center for Structural Biology (BE)
  • Inserm (FR)
Corresponding author
  • Caval, Vincent
  • Jouvenet, Nolwenn
ORCID
Venue
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2023-10-20
Volume
24
Issue
12
Pages
e57424-e57424
ISSN
  • 1469-221X (ISSN-L)
  • 1469-3178
DOI
10.15252/embr.202357424
PMC
PMC10702846
OpenAlex
W4387798834
Cited by
27
References
1
Citations by year
2026: 12 · 2025: 5 · 2024: 7 · 2023: 3
FWCI
2.96
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Reports (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
Funders
Agence Nationale de la Recherche (ANR‐19‐CE35‐0015, ANR‐20‐CE11‐0024)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Keywords
tick-borne flaviviruses, tick-borne encephalitis virus, louping ill virus, NS5 protein, RNA-dependent RNA polymerase, TYK2, interferon signaling, JAK/STAT signaling, interferon antagonism, kinase inhibition, protein-protein interaction, antiviral evasion
MeSH terms
Animals, Encephalitis Viruses, Tick-Borne, Humans, Interferons, Mammals, Ticks, Viral Nonstructural Proteins, TYK2 Kinase

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