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.

The transcription factor STAT1 is essential for interferon (IFN)-mediated immunity in humans and mice. STAT1 function is tightly regulated, and both loss-and gain-of-function mutations result in severe immune diseases. The two alternatively spliced isoforms, STAT1␣ and STAT1␤, differ with regard to a C-terminal transactivation domain, which is absent in STAT1␤. STAT1␤ is considered to be transcriptionally inactive and to be a competitive inhibitor of STAT1␣. To investigate the functions of the STAT1 isoforms in vivo, we generated mice deficient for either STAT1␣ or STAT1␤. As expected, the functions of STAT1␣ and STAT1␤ in IFN-␣/␤-and IFN--dependent antiviral activity are largely redundant. In contrast to the current dogma, however, we found that STAT1␤ is transcriptionally active in response to IFN-␥. In the absence of STAT1␣, STAT1␤ shows more prolonged IFN-␥-induced phosphorylation and promoter binding. Both isoforms mediate protective, IFN-␥-dependent immunity against the bacterium Listeria monocytogenes, although with remarkably different efficiencies. Our data shed new light on the potential contributions of the individual STAT1 isoforms to STAT1-dependent immune responses. Knowledge of STAT1␤'s function will help fine-tune diagnostic approaches and help design more specific strategies to interfere with STAT1 activity.

No abstract

No abstract

No abstract