Tick‐borne flavivirus NS5 antagonizes interferon signaling by inhibiting the catalytic activity of TYK2 - Archive ouverte HAL Access content directly
Journal Articles EMBO Reports Year : 2023

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

Sandrine Lacour
Manon Lemasson
  • Function : Author
Marion Sourisseau
Jennifer Richardson

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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Dates and versions

hal-04251902 , version 1 (27-10-2023)

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Ségolène Gracias, Maxime Chazal, Alice Decombe, Yves Unterfinger, Adrià Sogues, et al.. Tick‐borne flavivirus NS5 antagonizes interferon signaling by inhibiting the catalytic activity of TYK2. EMBO Reports, 2023, 24, pp.e57424. ⟨10.15252/embr.202357424⟩. ⟨hal-04251902⟩
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