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

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.