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.
Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which transduces cytokine and growth factor signalling. Analysis of TYK2 loss-of-function revealed its important role in immunity to infection, (auto-) immunity and (auto-) inflammation. TYK2-deficient patients unravelled high similarity between mice and men with respect to cellular signalling functions and basic immunology. Genome-wide association studies link TYK2 to several autoimmune and inflammatory diseases as well as carcinogenesis. Due to its cytokine signalling functions TYK2 was found to be essential in tumour surveillance. Lately TYK2 activating mutants and fusion proteins were detected in patients diagnosed with leukaemic diseases suggesting that TYK2 is a potent oncogene. Here we review the cell intrinsic and extrinsic functions of TYK2 in the characteristics preventing and enabling carcinogenesis. In addition we describe an unexpected function of kinase-inactive TYK2 in tumour rejection.
Interferons (IFNs) are key cytokines in the innate immune response that also bridge the gap to adaptive immunity. Signaling upon stimulation by IFN type I, II and III is mediated by the Jak-Stat pathway. STAT1 is activated by all three IFN receptor complexes and absence of STAT1 from mice increases their susceptibility to pathogens. In addition, depending on the setting, STAT1 can act as tumor suppressor or oncogene. Here we report the generation and detailed functional characterization of a conditional Stat1 knockout mouse. We show the integrity of the conditional Stat1 locus and report successful in vivo deletion by means of a ubiquitous and a tissue-specific Cre recombinase. The conditional Stat1 null allele represents an important tool for identifying novel and cell-autonomous STAT1 functions in infection and cancer.
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