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

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36 Citations (Scopus)

Abstract

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 (Tyk2K923E) 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 TYK2K923E in vitro. Tyk2K923E 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.

Original languageEnglish
Article numbere39141
JournalPloS one
Volume7
Issue number6
DOIs
Publication statusPublished - Jun 18 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Prchal-Murphy, M., Semper, C., Lassnig, C., Wallner, B., Gausterer, C., Teppner-Klymiuk, I., Kobolak, J., Müller, S., Kolbe, T., Karaghiosoff, M., Dinnyés, A., Rülicke, T., Leitner, N. R., Strobl, B., & Müller, M. (2012). TYK2 kinase activity is required for functional type I interferon responses in Vivo. PloS one, 7(6), [e39141]. https://doi.org/10.1371/journal.pone.0039141