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.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
Michaela
M
Prchal-Murphy
Christian
C
Semper
Caroline
C
Lassnig
Barbara
B
Wallner
Christian
C
Gausterer
Ingeborg
I
Teppner-Klymiuk
Julianna
J
Kobolak
Simone
S
Müller
Thomas
T
Kolbe
Marina
M
Karaghiosoff
Andras
A
Dinnyés
Thomas
T
Rülicke
Nicole R
NR
Leitner
Birgit
B
Strobl
Mathias
M
Müller
D056704:Adaptive Immunity / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004789:Enzyme Activation / Q000235:genetics; D023061:Gene Order; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007370:Interferon Type I / Q000494:pharmacology*; D016899:Interferon-beta / Q000276:immunology / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009928:Organ Specificity / Q000235:genetics; D055550:Protein Stability; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D007370:Interferon Type I; D050791:STAT Transcription Factors; D016899:Interferon-beta; D053612:Janus Kinases; D053634:TYK2 Kinase