1. TYK2 kinase activity is required for functional type I interferon responses in vivo
- Author
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Thomas Kolbe, Nicole R. Leitner, Michaela Prchal-Murphy, Barbara Wallner, Marina Karaghiosoff, Birgit Strobl, Ingeborg Teppner-Klymiuk, Christian Semper, Julianna Kobolák, Christian Gausterer, Caroline Lassnig, Mathias Müller, Simone Müller, Thomas Rülicke, and Andras Dinnyes
- Subjects
Mouse ,Adaptive Immunity ,Mice ,Gene Order ,Molecular Cell Biology ,Mice, Knockout ,Multidisciplinary ,Janus kinase 2 ,biology ,Janus kinase 1 ,Protein Stability ,Animal Models ,Innate Immunity ,Cell biology ,STAT Transcription Factors ,Tyrosine kinase 2 ,Organ Specificity ,Virus Diseases ,Gene Targeting ,Interferon Type I ,Medicine ,Signal Transduction ,Research Article ,Transcriptional Activation ,Science ,Immunology ,Model Organisms ,TYK2 Kinase ,Genetics ,Animals ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Biology ,Janus Kinases ,Base Sequence ,Cyclin-dependent kinase 4 ,Immunity ,Immune Defense ,Interferon-beta ,Protein kinase R ,Molecular biology ,Immunity, Innate ,Enzyme Activation ,Mutation ,biology.protein ,Cyclin-dependent kinase 9 ,Gene Function ,Janus kinase - 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 (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.
- Published
- 2012