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

Author

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, and Mathias Müller

Subjects
Medicine, Science
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
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2. TYK2 kinase activity is required for functional type I interferon responses in vivo

Author

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

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