PLoS ONE (Jan 2012)

TYK2 kinase activity is required for functional type I interferon responses in vivo.

  • Michaela Prchal-Murphy,
  • Christian Semper,
  • Caroline Lassnig,
  • Barbara Wallner,
  • Christian Gausterer,
  • Ingeborg Teppner-Klymiuk,
  • Julianna Kobolak,
  • Simone Müller,
  • Thomas Kolbe,
  • Marina Karaghiosoff,
  • Andras Dinnyés,
  • Thomas Rülicke,
  • Nicole R Leitner,
  • Birgit Strobl,
  • Mathias Müller

DOI
https://doi.org/10.1371/journal.pone.0039141
Journal volume & issue
Vol. 7, no. 6
p. e39141

Abstract

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Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive (Tyk2(K923E)) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein's stability. An inhibitory function was only observed upon over-expression of TYK2(K923E)in vitro. Tyk2(K923E) mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors.