TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo

Prchal-Murphy, Michaela; Semper, Christian; Lassnig, Caroline; Wallner, Barbara; Gausterer, Christian; Teppner-Klymiuk, Ingeborg; Kobolák, Julianna; Müller, Simone; Kolbe, Thomas; Karaghiosoff, Marina; Dinnyés, András; Rülicke, Thomas; Leitner, Nicole R.; Strobl, Birgit; Müller, Mathias

doi:10.1371/journal.pone.0039141

Cited by 66 publications

(63 citation statements)

References 63 publications

(107 reference statements)

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“…In line with this, GzmB and Prf1 expression were not altered in the absence of STAT1. 41 Similar to our earlier findings for IFNa/b 31 , we did not observe differences between Tyk2 ¡/¡ and Tyk2 K923E NK cells in canonical IL-12 signaling: STAT3 and STAT4 activation and IFNg production are severely impaired in both genotypes. We demonstrate that the requirement for TYK2 in the IL-12 signaling cascade is not due to an IL-12Rb1 scaffolding function.…”

Section: Discussionsupporting

confidence: 90%

“…31 For pJAK2 analysis cells were lysed directly in 1 £ Laemmli sample buffer. Antibodies used were: pSTAT3 (Tyr705, CS#9131), STAT3 (CS#9132S), STAT4 (clone C46B10, CS#2653), pJAK2 (Tyr1008, D4A8, CS#8082), JAK2 (D2E12, CS#3230), GzmB (CS#4275) and Prf1 (CS#3693) all from Cell Signaling Technology; panERK (clone 16/ERK) and pSTAT4 (Tyr693, clone 38/pSTAT4) from BD Transduction Laboratories.…”

Section: Western Blotmentioning

confidence: 99%

“…31 In this study, we further investigated the role of TYK2 in NK cells and tumor immune surveillance and present the first evidence for kinase-independent functions of TYK2 in vivo.…”

Section: Introductionmentioning

confidence: 99%

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In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

et al. 2015

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Abbreviations: CCL3, chemokine (C-C motif) ligand 3; CFSE, carboxyfluorescein diacetate succinimidyl ester; GzmB, granzyme B; IFN, interferon; IFNAR, interferon a and b receptor; IL, interleukin; IL-12Rb1, interleukin-12 receptor subunit b-1; iNK, immature natural killer; JAK, xJanus kinase; MACS, magnetic-activated cell sorting; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; miR, microRNA; mNK, mature natural killer; NK, natural killer; NKP, natural killer precursor; Prf1, perforin; SEM, standard error of the mean; STAT, signal transducer and activator of transcription; T-ALL, T cell acute lymphoblastic leukemia; TYK2, tyrosine kinase 2; TYK2 K923E , kinase-inactive tyrosine kinase 2; WT, wild-typeTyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2 ¡/¡ ) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2 ¡/¡ mice and mice expressing a kinase-inactive version of TYK2 (Tyk2 K923E ), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2 ¡/¡ and Tyk2 K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2 ¡/¡ NK cells (and to a lesser extent of Tyk2 K923E NK cells) is impaired. In contrast, the production of interferon g (IFNg) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2 K923E NK cells against a range of target cells in vitro is higher than that of Tyk2 ¡/¡ NK cells. Consistently, Tyk2 K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2's kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy.

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Section: Discussionsupporting

confidence: 90%

Section: Western Blotmentioning

confidence: 99%

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In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

et al. 2015

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“…Recently, a kinase-inactive Tyk2 mouse line was published in which noncanonical, kinase-independent functions could not be observed with regard to type I IFN response and antiviral defense. 40 However, in line with our data, noncatalytic functions of human Jak1 and Tyk2 in the context of IFNAR1, IL-6, and IL-10 stimulation were reported, suggesting that 1 catalytically competent Jak is sufficient for signaling provided that its partner behaves as scaffold, even if inactive. 41,42 Investigation of a Jak3 activation-loop-defective mutant, YY1980/981FF, demonstrates that activation-loop tyrosines are not absolutely required for Jak3 catalytic function, whereas lysine mutation (K885A) in the ATP-binding pocket completely abrogates catalytic activity.…”

Section: /2supporting

confidence: 87%

Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation-loop mutation

Keil

Finkenstädt

Wufka

et al. 2014

Blood

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“…Studies in mice have shown that the requirement for Tyk2 in signaling by type I IFN and other immune cytokines can be cellcontext dependent (2,3,53). Moreover, it is increasingly clear that the functional impact of many polymorphisms, notably in immune response imbalance, can differ according to cell or tissue types and their particular biological state.…”

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confidence: 99%

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Gakovic

Ragimbeau

et al. 2013

The Journal of Immunology

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Tyk2 belongs to the Janus protein tyrosine kinase family and is involved in signaling of immunoregulatory cytokines (type I and III IFNs, IL-6, IL-10, and IL-12 families) via its interaction with shared receptor subunits. Depending on the receptor complex, Tyk2 is coactivated with either Jak1 or Jak2, but a detailed molecular characterization of the interplay between the two enzymes is missing. In human populations, the Tyk2 gene presents high levels of genetic diversity with >100 nonsynonymous variants being detected. In this study, we characterized two rare Tyk2 variants, I684S and P1104A, which have been associated with susceptibility to autoimmune disease. Specifically, we measured their in vitro catalytic activity and their ability to mediate Stat activation in fibroblasts and genotyped B cell lines. Both variants were found to be catalytically impaired but rescued signaling in response to IFN-α/β, IL-6, and IL-10. These data, coupled with functional study of an engineered Jak1 P1084A, support a model of nonhierarchical activation of Janus kinases in which one catalytically competent Jak is sufficient for signaling provided that its partner behaves as proper scaffold, even if inactive. Through the analysis of IFN-α and IFN-γ signaling in cells with different Jak1 P1084A levels, we also illustrate a context in which a hypomorphic Jak can hamper signaling in a cytokine-specific manner. Given the multitude of Tyk2-activating cytokines, the cell context–dependent requirement for Tyk2 and the catalytic defect of the two disease-associated variants studied in this paper, we predict that these alleles are functionally significant in complex immune disorders.

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TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo

Cited by 66 publications

References 63 publications

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation-loop mutation

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

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