Fine-tuning the reverse genetics of Tyk2

NETWORK CONTRIBUTION

The Janus kinase (Jak) Tyk2 is an important determinant in host immunity both in mice and in humans. Tyk2 deficiency results in increased sensitivity to microbial infections and increased tumor development but improves clinical symptoms in several autoimmune and inflammatory diseases. Tyk2 inhibitors are in development and are considered to be promising tools for the treatment of human diseases, including psoriasis, rheumatoid arthritis and inflammatory bowel disease. However, several lines of evidence suggest that Jaks may have kinase-independent activities, e.g. receptor stabilizing and adapter functions.

Our major goals are to dissect kinase-dependent and -independent functions of Tyk2 in vivo. During the previous funding periods we have generated mice that express a kinase-inactive Tyk2 protein (Tyk2K923E) and could confirm our hypothesis that the lack of Tyk2 kinase activity does not phenocopy Tyk2 deficiency. Unexpectedly, we found that kinase-inactive Tyk2 contributes to tumor surveillance and our results point towards an involvement of natural killer (NK) cells in the process. In contrast, Tyk2 kinase activity is essential for canonical type I interferon (IFNα/β) signaling and to control viral infections in vivo.

The most prominent defect in Tyk2-/- mice is impaired interleukin-12 (IL-12) signaling and a consequent failure to produce IFNγ upon a wide range of immunological challenges. This defect crucially contributes to both the increased sensitivity to infections and the resistance against inflammatory diseases. It may also account, at least partially, for the defective tumor surveillance observed in Tyk2-/- mice. IL-12 signaling is similarly impaired in Tyk2-/- and Tyk2K923E lymphocytes but surprisingly we found Tyk2 kinase-independent, delayed IFNγ production after Listeria monocytogenes infection in vivo.

Within the proposed project part we aim to determine how kinase-inactive Tyk2 contributes to NK cell activity and tumor surveillance. Furthermore, we aim at further dissecting kinase-dependent and -independent functions of Tyk2 in the regulation of IFN production and during innate and adaptive immune responses to L. monocytogenes infections.

CONTACT

Department of Biomedical Sciences, Institute of Animal Breeding and Genetics
University of Veterinary Medicine Vienna, Vetmeduni Vienna

A-1210 Vienna
Austria

mathias.mueller@vetmeduni.ac.at

HYPOTHESES

Immune surveillance

Kinase-inactive Tyk2 contributes to NK cell- but not CD8+ T cell-mediated tumor immune surveillance.

NK cell maturation

Kinase-dependent and -independent functions of Tyk2 control NK cell development/maturation and/or NK cell cytotoxicity.

IFNγ independence

The presence of kinase-inactive Tyk2 impairs innate IFNγ production but triggers alternative adaptive immune cell activation, or (b) kinase-inactive Tyk2 blocks negative immune regulatory pathways acting on IFNγ-producing cells.

Adaptive immunity

Kinase-inactive Tyk2 can contribute to the control of low-dose L. monocytogenes infection and to the development of adaptive immunity.

PUBLICATIONS

SFB-F61 / F28 related publications - Group Müller

Sauer, I., Schaljo, B., Vogl, C., Gattermeier, I., Kolbe, T., Müller, M., Blackshear, P.J. and Kovarik, P. (2006).
Interferons limit inflammatory responses by induction of tristetraprolin.
Blood 107:4790-7. doi: http://dx.doi.org/10.1182/blood-2005-07-3058
Leitner, N.R., Strobl§, B., Bokor, M., Painz, R., Kolbe, T., Rülicke, T., Müller, M. and Karaghiosoff, M. (2006). §SFB member of the 2nd and 3rd funding period
A time- and dose-dependent STAT1 expression system.
BMC Biotechnol 6:48. doi: 10.1186/1472-6750-6-48
Gausterer, C., Müller, M., and Strobl§, B. (2007). §SFB member of the 2nd and 3rd funding period
In vivo target validation: Methodology and Case Studies on the Janus kinase Tyk2.
Anti-Inflammatory & Anti-Allergy Agents in Medical Chemistry 6, 29-45. doi: 10.2174/187152307779939697
Painz, R., Walter, I., Kolbe, T., Rigler, D., Vogl, C., Steinborn, R., Rülicke, T., Helmreich, M., Karaghiosoff, M. and Müller, M. (2007).
Organ-specific and differential requirement of TYK2 and IFNAR1 for LPS-induced iNOS expression in vivo.
Immunobiol 212:863-75. doi: 10.1016/j.imbio.2007.09.017
Grebien, F., Kerenyi, M.A., Kovacic, B., Kolbe, T., Becker, V., Dolznig, H., Pfeffer, K., Klingmuller, U., Müller, M., Beug, H., Müllner*, E.W. and Moriggl*, R. (2008). *equal contribution and equal correspondence
Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2.
Blood 111:4511-22. doi: http://dx.doi.org/10.1182/blood-2007-07-102848
Reutterer, B., Stockinger, S., Pilz, A., Soulat, S., Kastner, R., Westermayer, S., Rülicke, T., Müller, M. and Decker, T. (2008).
Type I IFN are host modulators of strain-specific Listeria monocytogenes virulence.
Cell Microbiol 10:1116-29. doi: 10.1111/j.1462-5822.2007.01114.x
Schuster, C., Müller, M., Freissmuth, M., Sexl, V. and Stoiber, D. (2008).
Commentary on H.Ide et al: “Tyk2 expression and its signaling enhances invasiveness of prostate cancer cells”.
Biochem Biophys Res Commun 366:869-70. doi: 10.1016/j.bbrc.2007.12.017
Kornfeld, J.W., Grebien, F., Kerenyi, M.A., Friedbichler, K., Kovacic, B., Zankl, B., Hoelbl, A., Nivarti, H., Beug, H., Sexl, V., Müller, M., Kenner, L., Müllner, E.W., Gouilleux, F. and Moriggl, R. (2008).
The different functions of Stat5 and chromatin alteration through Stat5 proteins.
Front Biosci 13:6237-54. [review] doi: dx.doi.org/10.2741/3151
Costantino, G., Egerbacher, M., Kolbe, T., Karaghiosoff, M., Strobl§, B., Vogl, C., Helmreich, M. and Müller, M. (2008). §SFB member of the 2nd and 3rd funding period
Tyk2 and signal transducer and activator of transcription 1 contribute to intestinal I/R injury.
Shock 29:238-44. doi: 10.1097/shk.0b013e3180cab252
Grunert, T., Marchetti-Deschmann, M., Miller, I., Müller, M. and Allmaier, G. (2008).
Comparing the applicability of CGE-on-the-chip and SDS-PAGE for fast pre-screening of mouse serum samples prior to proteomics analysis.
Electrophoresis 29:4332-40. doi: 10.1002/elps.200800035
Radwan, M., Miller, I., Grunert, T., Marchetti-Deschmann, M., Vogl, C., O'Donoghue, N., Dunn, M. J., Kolbe, T., Allmaier, G., Gemeiner, M., Müller, M. and Strobl§, B. (2008). §SFB member of the 2nd and 3rd funding period
The impact of tyrosine kinase 2 (Tyk2) on the proteome of murine macrophages and their response to lipopolysaccharide (LPS).
Proteomics 8:3469-85. doi: 10.1002/pmic.200800260
Schneider, A., Reichart, U., Gerner, W., Kolbe, T., Saalmüller, A. and Müller, M. (2008).
Selective contribution of Tyk2 to cell activation by lipopolysaccharide.
FEBS Lett 582:3681-6. doi: 10.1016/j.febslet.2008.09.053
Weichhart, T., Costantino, G., Poglitsch, M., Rosner, M., Zeyda, M., Stuhlmeier, K.M., Kolbe, T., Stulnig, T.M., Horl, W.H., Hengstschlager, M., Müller, M. and Saemann, M.D. (2008).
The TSC-mTOR signaling pathway regulates the innate inflammatory response.
Immunity 29:565-77. doi: http://dx.doi.org/10.1016/j.immuni.2008.08.012
Pilz, A., Kratky, W., Stockinger, S., Simma, O., Kalinke, U., Lingnau, K., von Gabain, A., Stoiber, D., Sexl, V., Kolbe, T., Rulicke, T., Müller, M. and Decker, T. (2009).
Dendritic cells require STAT-1 phosphorylated at its transactivating domain for the induction of peptide-specific CTL.
J Immunol 183:2286-93. doi: 10.4049/jimmunol.0901383
Prchal, M, Pilz, A., Simma, O., Lingnau, K., von Gabain, A., Strobl, B., Müller, M., and Decker, T. (2009).
Type I interferons as mediators of immune adjuvants for T- and B cell- dependent acquired immunity.
Vaccine 27 Suppl 6, G17-20. doi: 10.1016/j.vaccine.2009.10.016
Schaljo, B., Kratochvill, F., Gratz, N., Sadzak, I., Sauer, I., Hammer, M., Vogl, C., Strobl, B., Müller, M., Blackshear, P.J., Poli, V., Lang, R., Murray, P.J. and Kovarik, P. (2009).
Tristetraprolin is required for full anti-inflammatory response of murine macrophages to IL-10.
J Immunol 183:1197-206. doi: 10.4049/jimmunol.0803883
Simma, O., Zebedin, E., Neugebauer, N., Schellack, C., Pilz, A., Chang-Rodriguez, S., Lingnau, K., Weisz, E., Putz, E.M., Pickl, W.F., Felzmann, T., Müller, M., Decker, T., Sexl, V. and Stoiber, D. (2009).
Identification of an indispensable role for tyrosine kinase 2 in CTL-mediated tumor surveillance.
Cancer Res 69:203-11. doi: 10.1158/0008-5472.CAN-08-1705
Stockinger, S., Kastner, R., Kernbauer, E., Pilz, A., Westermayer, S., Reutterer, B., Soulat, D., Stengl, G., Vogl, C., Frenz, T., Waibler, Z., Taniguchi, T., Rulicke, T., Kalinke, U., Müller, M. and Decker, T. (2009).
Characterization of the interferon-producing cell in mice infected with Listeria monocytogenes.
PLoS Pathog 5, e1000355. doi: 10.1371/journal.ppat.1000355
Farlik, M., Reutterer, B., Schindler, C., Greten, F., Vogl, C., Müller, M., and Decker, T. (2010).
Nonconventional Initiation Complex Assembly by STAT and NF-kappaB Transcription Factors Regulates Nitric Oxide Synthase Expression.
Immunity 33: 25-34. doi: 10.1016/j.immuni.2010.07.001
Musteanu, M., Blaas, L., Mair, M., Schlederer, M., Bilban, M., Tauber, S., Esterbauer, H., Mueller, M., Casanova, E., Kenner, L., Poli, V., and Eferl, R. (2010).
Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice.
Gastroenterology 138: 1003-1011. doi: 10.1053/j.gastro.2009.11.049
Radwan*, M., Stiefvater*, R., Grunert, T., Sharif, O., Miller, I., Marchetti-Deschmann, M., Allmaier, G., Gemeiner, M., Knapp, S., Kovarik§, P., Müller, M., and Strobl, B. (2010). *equal contribution §SFB member of the 1st funding period
Tyrosine kinase 2 controls IL-1beta production at the translational level.
J Immunol 185: 3544-3553. doi: 10.4049/jimmunol.0904000
Vogl, C., Flatt, T., Fuhrmann, B., Hofmann, E., Wallner, B., Stiefvater, R., Kovarik, P., Strobl, B., and Müller, M. (2010).
Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes.
BMC Genomics 11: 199. doi: 10.1186/1471-2164-11-199
Bourgeois, C., Majer, O., Frohner, I.E., Lesiak-Markowicz, I., Hildering, K.S., Glaser, W., Stockinger, S., Decker, T., Akira, S., Müller, M., and Kuchler, K. (2011).
Conventional dendritic cells mount a type I interferone response against Candida spp requiring novel phagosomal TLR7 mediated IFN-β signaling.
J Immunol 186, 3104-3112. doi: 10.4049/jimmunol.1002599
Eckelhart, E., Warsch, W., Zebedin, E., Simma, O., Stoiber, D., Kolbe, T., Rulicke, T., Mueller, M., Casanova, E., and Sexl, V. (2011).
A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK cell survival and development.
Blood 117: 1565-1573. doi: dx.doi.org/10.1182/blood-2010-06-291633
Schneckenleithner, C., Bago-Horvath, Z., Dolznig, H., Neugebauer, N., Kollmann, K., Kolbe, T., Decker, T., Kerjaschki, D., Wagner, K.-U., Müller, M., Stoiber, D., and Sexl, V. (2011).
Putting the brakes on mammary tumorigenesis: Loss of STAT1 predisposes to intraepithelial neoplasias.
Oncotarget 2: 1043-1054. online ISSN: 1949-2553
Schuster*, C., Berger*, A., Hoelzl, M.A., Putz, E.M., Frenzel, A., Simma, O., Moritz, N., Hoelbl, A., Kovacic, B., Freissmuth, M., Müller, M., Villunger, A., Mullauer, L., Schmatz, A.I., Streubel, B., Porpaczy, E., Jager, U., Stoiber, D., and Sexl, V. (2011). *equal contribution
The cooperating mutation or "second hit" determines the immunological visibility towards MYC-induced murine lymphomas.
Blood 118: 4635-4645. doi: http://dx.doi.org/10.1182/blood-2010-10-313098
Strobl, B., Stoiber, D., Sexl, V., and Müller, M. (2011).
Tyrosine kinase 2 (Tyk2) in cytokine signalling and host immunity.
Front Biosci 17: 3224-3232. [review] doi: http://dx.doi.org/10.2741/3908
Kratochvill, F., Machacek, C., Vogl, C., Ebner, F., Sedlyarov, V., Gruber, A.R., Hartweger, H., Vielnascher, R., Karaghiosoff, M., Rülicke, T., Müller, M., Hofacker, I., Lang, R., and Kovarik§, P. (2011). §SFB member of the 1st funding period
Tristetraprolin-driven regulatory circuit controls quality and timing of mRNA decay in inflammation.
Mol Sys Biol 7: 560. doi: 10.1038/msb.2011.93
Blanc, M., Hsieh, W., Robertson, K., Watterson, S., Shui, G., Lacaze, P., Khondoker, M., Dickinson, P., Sing, G., Rodriguez-Martin, S., Phelan, P., Forster, T., Strobl, B., Müller, M., Riemersma, R., Osborne, T., Wenk, M.R., Angulo, A., and Ghazal, P. (2011).
Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis.
PLoS Biol 9: e1000598. doi: 10.1371/journal.pbio.1000598
Grunert, T., Leitner, N.R., Marchett-Deschmann, M., Miller, I., Wallner, B., Radwan, M., Vogl, C., Kolbe, T., Kratky, D., Gemeiner, M., Allmaier, G., Müller, M., and Strobl, B. (2011).
A comparative proteome analysis links tyrosine kinase 2 (Tyk2) to the regulation of cellular glucose and lipid metabolism in response to poly(I:C).
J Proteomics 74: 2866-2880. doi: 10.1016/j.jprot.2011.07.006
Kropp, K.A., Robertson, K.A., Sing, G., Rodriguez-Martin, S., Blanc, M., Lacaze, P., Noor Hassim, M.F.B., Khondoker, M.R., Busche, A., Dickinson, P., Forster, T., Strobl, B., Müller, M., Jonjic, S., Angulo, A., and Ghazal, P. (2011).
Reversible inhibition of MCMV replication by IFN{gamma} in primary macrophages involves a primed type I IFN signaling sub-network for full establishment of an immediate-early antiviral-state.
J Virol 85: 10286-10299. doi: 10.1128/JVI.00373-11
Pichlmair, A., Lassnig, C., Eberle, C.-A., Górna, M.W., Baumann, C.L., Burkard, T.R., Bürckstümmer, T., Stefanovic, A., Krieger, S., Bennet, K.L., Rülicke, T., Weber, F., Colinge, J., Müller, M., and Superti-Furga, G. (2011).
IFIT1 is an antiviral protein that recognizes 5’-triphosphate RNA.
Nat Immunol 12: 624-630. doi: 10.1038/ni.2048
Todoric, J., Strobl, B., Jais, A., Boucheron, N., Bayer, M., Amman, S., Lindroos, J., Teperino, R., Prager, G., Bilban, M., Ellmeier, W., Krempler, F., Müller, M., Wagner, O., Patsch, W., Pospsilik, J.A., and Esterbauer, H. (2011).
Cross-Talk Between Interferon-{gamma} and Hedgehog Signaling Regulates Adipogenesis.
Diabetes 60: 1668-1676. doi: 10.2337/db10-1628
Weichhart, T., Haidinger, M., Katholnig, K., Kopecky, C., Poglitsch, M., Lassnig, C., Rosner, M., Zlabinger, G.J., Hengstschläger, M., Müller, M., Hörl, W., and Säemann, M.D. (2011).
Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells.
Blood 117: 4273-4283. doi: http://dx.doi.org/10.1182/blood-2010-09-310888
Hofmann, E., Reichart, U., Gausterer, C., Gülly, C., Meijer, D., Müller, M., and Strobl, B. (2010).
Octamer-binding factor 6 (Oct-6/Pou3f1) is induced by interferon and contributes to dsRNA-mediated transcriptional responses.
BMC Cell Biol 11: 61. doi: 10.1186/1471-2121-11-61
Putz*, E.M., Prchal-Murphy*, M., Simma, O.A., Forster, F., Koenig, X., Stockinger, H., Piekorz, R.P., Freissmuth, M., Müller, M., Sexl, V., and Zebedin-Brandl, E. (2012). *equal contribution
PI3Kδ Is Essential for Tumor Clearance Mediated by Cytotoxic T Lymphocytes.
PLoS One 7: e40852. doi: 10.1371/journal.pone.0040852
Friedbichler, K., Themanns, M., Mueller, K.M., Schlederer, M., Kornfeld, J.-W., Terracciano, L.M., Kozlov, A.V., Haindl, S., Kenner, L., Kolbe, T., Mueller, M., Snibson, K., Heim, M.H., and Moriggl, R. (2012).
Growth hormone-induced STAT5 signaling causes gigantism, inflammation and premature death but protects mice from aggressive liver cancer.
Hepatology 55: 941-952. doi: 10.1002/hep.24765
Kernbauer, E., Maier, V., Stoiber, D., Strobl, B., Schneckenleithner, C., Sexl, V., Reichart, U., Kalinke, U., Reizis, B., Jamieson, A., Müller, M., and Decker, T. (2012).
Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection.
PLoS Pathog 8: e1002763. doi: 10.1371/journal.ppat.1002763
Mizutani*, T., Neugebauer*, N., Putz*, E.M., Moritz, N., Simma, O., Zebedin-Brandl, E., Gotthardt, D., Warsch, W., Eckelhart, E., Kantner, H.-P., Kalinke, U., Lienenklaus, S., Weiss, S., Strobl, B., Müller, M., Sexl, V., and Stoiber, D. (2012). *equal contribution
Conditional IFNAR1 ablation reveals distinct requirements of Type I IFN signaling for NK cell maturation and tumor surveillance.
Oncoimmunology 1: 1027-1037. doi: 10.4161/onci.21284
Musteanu, M., Blaas, L., Zenz, R., Svinka, J., Hoffmann, T., Grabner, B., Schramek, D., Kantner, H.P., Müller, M., Kolbe, T., Rülicke, T., Moriggl, R., Kenner, L., Stoiber, D., Penninger, J., Popper, H., Casanova, E., and Eferl, R. (2012).
A mouse model to identify cooperating signaling pathways in cancer.
Nat Methods 9: 897-900. doi: 10.1038/nmeth.2130
Prchal-Murphy, M., Semper, C., Lassnig, C., Wallner, B., Gausterer, C., Teppner-Klymiuk, I., Kobolak, J., Müller, S., Kolbe, T., Karaghiosoff, M., Dinnyes, A., Rülicke, T., Leitner, N.R., Strobl, B., and Müller, M. (2012).
TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo.
PLoS One 7: e39141. doi: 10.1371/journal.pone.0039141
Wallner*, B., Leitner*, N.R., Vielnascher, R.M., Kernbauer, E., Kolbe, T., Karaghiosoff, M., Rülicke, T., Decker, T., and Müller, M. (2012). *equal contribution
Generation of mice with a conditional Stat1 null allele.
Transgenic Res 21: 217-224. doi: 10.1007/s11248-011-9519-5
Decker, T., and Müller, M. (2012).
Jak-Stat Signaling: From Basics to Disease.
Jak-Stat Signaling: From Basics to Disease. Springer Wien Heidelberg New York Dordrecht London. 448 p. 45 illus. [book] doi: 10.1007/978-3-7091-0891-8_1 ISBN: 978-3-7091-0890-1
Decker, T., and Müller, M. (2012)
The Continuing Fascination with Jaks and Stats: An Introduction.
Jak-Stat Signaling: From Basics to Disease. Springer Wien Heidelberg New York Dordrecht London. pp. 1-4. [book chapter] doi: 10.1007/978-3-7091-0891-8_1
Rampetsreiter, P. and Eferl, R. (2012).
STAT1 and STAT3 Transcription Factors in Inflammation-Associated Colon Cancer.
In Jak-Stat Signaling: From Basics to Disease. (Decker, T. and Müller, M. Eds.) Springer Wien Heidelberg New York Dordrecht London. pp. 289-304. [book chapter] doi: 10.1007/978-3-7091-0891-8_16 ISBN: 978-3-7091-0890-1
Nivarthi, H., Friedbichler, K., and Moriggl, R. (2012).
Stat5 as a Hematopoietic Master Regulator for Differentiation and Neoplasia Development.
In Jak-Stat Signaling: From Basics to Disease. (Decker, T. and Müller, M., Eds.) Springer Wien Heidelberg New York Dordrecht London. pp. 153-168. [book chapter] doi: 10.1007/978-3-7091-0891-8_10 ISBN: 978-3-7091-0890-1
Majer, O., Bourgeois, C., Zwolanek, F., Lassnig, C., Kerjaschiki, D., Mack, M., Müller, M., and Kuchler, K. (2012).
Type I Interferons Promote Fatal Immunopathology by Regulating Inflammatory Monocytes and Neutrophils during Candida Infections.
PLoS Pathog 8: e1002811. doi: 10.1371/journal.ppat.1002811
Strobl, B., Leitner, N.R., and Müller, M. (2012).
Multifaceted Antiviral Actions of Interferon-Stimulated Gene Products.
In Jak-Stat Signaling: From Basics to Disease. (Decker, T. and Müller, M., Eds.) Springer Wien Heidelberg New York Dordrecht London. pp. 387-424. [book chapter] doi: 10.1007/978-3-7091-0891-8_21 ISBN: 978-3-7091-0890-1
Putz, E.M., Zebedin, E., and Sexl, V. (2012).
STAT Transcription Factors: Controlling All Aspects of NK Cell Biology.
In Jak-Stat Signaling: From Basics to Disease (Decker, T. and Müller, M., Eds.) Springer Wien Heidelberg New York Dordrecht London. pp. 187-204. [book chapter] doi: 10.1007/978-3-7091-0891-8_12 ISBN: 978-3-7091-0890-1
Rauch, I., Müller, M., and Decker, T. (2013).
The regulation of inflammation by interferons and their STATs.
JAK-STAT 2:1, e23820. [review] doi: 10.4161/jkst.23820
Kernbauer*, E., Maier*, V., Rauch, I., Müller, M. and Decker, T. (2013). *equal contribution
Route of infection determines the impact of type I interferons on innate immunity to Listeria monocytogenes.
PLoS One 8: e65007. doi: 10.1371/journal.pone.0065007
Köprülü, A.D., Kastner, R., Wienerroither, S., Lassnig, C., Putz, E.-M., Majer, O., Reutterer, B., Sexl, V., Kuchler, K., Müller, M., Decker, T., and Ellmeier, W. (2013).
The tyrosine kinase Btk regulates the macrophage response to Listeria monocytogenes infection.
PLoS One 8: e60476. doi: 10.1371/journal.pone.0060476
Putz, E.M., Gotthardt, D., Hoermann, G., Csiszar, A., Wirth, S., Berger, A., Straka, E., Rigler, D., Wallner, B., Jamieson, A.M., Pickl, W.F., Zebedin-Brandl, E.M., Müller, M., Decker, T., and Sexl, V. (2013).
CDK8-Mediated STAT1-S727 Phosphorylation Restrains NK Cell Cytotoxicity and Tumor Surveillance.
Cell Rep 15: 437-444. doi: 10.1016/j.celrep.2013.07.012
Sanda, T., Tyner, J.W., Gutierrez, A., Ngo, V.N., Glover, J., Chang, B.H., Yost, A., Ma, W., Fleischman, A.G., Zhou, W., Yang, Y., Kleppe, M., Ahn, Y., Tatarek, J., Kelliher, M., Neuberg, D., Levine, R.L., Moriggl, R., Müller, M., Gray, N.S., Jamieson, C.H., Weng, A.P., Staudt, L.M., Druker, B.J., and Look, A.T. (2013).
TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia.
Cancer Discov 3: 564-577. doi: 10.1158/2159-8290.CD-12-0504
Warszawska, J.M., Gawish, R., Sharif, O., Sigel, S., Doninger, B., Lakovits, K., Mesteri, I., Nairz, M., Boon, L., Spiel, A., Fuhrmann, V., Strobl, B., Müller, M., Schenk, P., Weiss, G., and Knapp, S. (2013).
Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes.
J Clin Invest 123: 3363-3372. doi: 10.1172/JCI67911
Bancerek, J., Poss, Z.C., Steinparzer, I., Sedlyarov, V., Pfaffenwimmer, T., Mikulic, I., Dölken, L., Strobl, B., Müller, M., Taatjes, D.J., and Kovarik§, P. (2013). §SFB member of the 1st funding period
CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response.
Immunity 38: 250-262. doi: 10.1016/j.immuni.2012.10.017
Katholnig, K., Kaltenecker, C.C., Hayakawa, H., Rosner, M., Lassnig, C., Zlabinger, G.J., Gaesetl, M., Müller, M., Hengstschläger, M., Hörl, W.H., Park, J.-M., Säemann, M.D., and Weichart, T. (2013).
p38α Senses Environmental Stress To Control Innate Immune Responses via Mechanistic Target of Rapamycin.
J Immunol 190: 1519-1527. doi: 10.4049/jimmunol.1202683
Bosmann, M., Russkamp, N.F., Strobl, B., Roewe, J., Balouzian, L., Pache, F., Radsak, M.P., van Rooijen, N., Zetoune, F.S., Sarma, J.V., Núnez, G., Müller, M., Murray, P.J., and Ward, P.A. (2014).
Interruption of macrophage-derived IL-27(p28) production by IL-10 during sepsis requires STAT3 but not SOCS3.
J Immunol 193: 5668-5677. doi: 10.4049/jimmunol.1302280
Bosmann, M., Strobl, B., Kichler, N., Pache, F., Murray, P.J., Müller, M., and Ward, P.A. (2014).
Tyrosine kinase 2 promotes sepsis-associated lethality by facilitating production of interleukin-27.
J Leukoc Biol. 96: 123-131. doi: 10.1189/jlb.3A1013-541R
Gotthardt, D., Putz, E.M., Straka, E., Kudweis, P., Biaggio, M., Poli, V., Strobl, B., Müller, M., and Sexl, V. (2014).
Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance.
Blood 124: 2370-2379. doi: http://dx.doi.org/10.1182/blood-2014-03-564450
Grunert, T., Monahan, A., Lassnig, C., Vogl, C., Strobl, B., Müller, M., and Ehling-Schulz, M. (2014).
Deciphering host genotype-specific impacts on the metabolic fingerprint of Listeria monocytogenes by FTIR spectroscopy.
PLoS One 9: e115959. doi: 10.1371/journal.pone.0115959
Keil, E., Finkenstädt, D., Wufka, C., Trilling, M., Liebfried, P., Strobl, B., Müller, M., and Pfeffer, K. (2014).
Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation loop mutation.
Blood 123: 520-529. doi: http://dx.doi.org/10.1182/blood-2013-03-492157
Kovacic, B., Hoelbl-Kovacic, A., Fischhuber, K.M., Leitner, N.R., Gotthardt, D., Casanova, E., Sexl, V., and Müller, M. (2014).
Lactotransferrin-Cre reporter mice trace neutrophils, monocytes/macrophages and distinct subtypes of dendritic cells.
Haematologica 99: 1006-1015. doi: 10.3324/haematol.2013.097154
Leitner, N.R., Lassnig, C., Rom, R., Heider, S., Bago-Horvath, Z., Eferl§, R., Müller, S., Kolbe, T., Kenner, L., Rülicke, T., Strobl, B., and Müller, M. (2014). §SFB member of the 1st and 2nd funding period
Inducible, dose-adjustable and time-restricted reconstitution of Stat1 deficiency in vivo.
PLoS One 9: e86608. doi: 10.1371/journal.pone.0086608
Liehl, P., Zuzarte-Luís, V., Chan, J., Zillinger, T., Baptista, F., Carapau, D., Konert, M., Hanson, K.K., Carret, C., Lassnig, C., Müller, M., Kalinke, U., Saeed, M., Ferreira Chora, A., Golenbock, D.T., Strobl, B., Prudencio, M., Coelho, L.P., Kappe, S.H., Superti-Furga, J., Pichlmair, A., Vigário, A.M., Rice, C.M., Fitzgerald, K.A., Barchert, W., and Mota, M.M. (2014).
Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection.
Nat Med 20: 47-53. doi: 10.1038/nm.342
Semper, C., Leitner, N.R., Lassnig, C., Parrini, M., Mahlakoiv, T., Rammerstorfer, M., Lorenz, K., Rigler, D., Müller, S., Kolbe, T., Vogl, C., Rülicke, T., Staeheli, P., Decker, T., Müller, M., and Strobl, B. (2014).
STAT1β is not dominant negative and is capable of contributing to IFNγ-dependent innate immunity.
Mol Cell Biol 34: 2235-2248. doi: 10.1128/MCB.00295-14
Vielnascher, R.M., Hainzl, E., Leitner, N.R., Rammerstorfer, M., Popp, D., Witalisz, A., Rom, R., Karaghiosoff, M., Kolbe, T., Müller, S., Rülicke, T., Lassnig, C., Strobl, B., and Müller, M. (2014).
Conditional ablation of TYK2 in immunity to viral infection and tumor surveillance.
Transgenic Res. 23: 519-529. doi: 10.1007/s11248-014-9795-y
Wienerroither, S., Rauch, I., Rosebrock, F., Jamieson, A.M., Bradner, J., Muhar, M., Zuber, J., Müller, M., and Decker, T. (2014).
Regulation of NO synthesis, local inflammation and innate immunity to pathogens by BET family proteins.
Mol Cell Biol 34: 415-427. doi: 10.1128/MCB.01353-13
Gilbert*, S., Nivarthi*, H., Mayhew*, C.N., Lo, Y.H., Noah, T.K., Vallance, J., Rulicke, T., Müller, M., Jegga, A.G., Tang, W., Zhang, D., Helmrath, M., Shroyer, N., Moriggl, R., and Han, X. (2015). *equal contribution
Activated STAT5 Confers Resistance to Intestinal Injury by Increasing Intestinal Stem Cell Proliferation and Regeneration.
Stem Cell Rep 4: 209-225. doi: 10.1016/j.stemcr.2014.12.004
Pathria*, P., Gotthardt*, D., Prchal-Murphy*, M., Putz*, E.M., Holcmann, M., Schlederer, M., Grabner, B., Crncec, I., Svinka, J., Musteanu, M., Hoffmann, T., Filipits, M., Berger, W., Poli, V., Kenner, L., Bilban, M., Casanova, E., Müller, M., Strobl, B., Bayer, E., Mohr, T., Sexl, V., and Eferl§, R. (2015). *equal contribution §SFB member of the 1st and 2nd funding period
Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice.
Oncoimmunology 4(4):e998529. doi: 10.1080/2162402X.2014.998529
Prchal-Murphy, M., Witalisz-Siepracka, A., Bednarik, K.T., Putz, E.M., Gotthardt, D., Meissl, K., Sexl, V., Müller, M., and Strobl, B. (2015).
In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity.
Oncoimmunology. doi: 10.1080/2162402X.2015.1047579
Rauch, I., Rosebrock, F., Hainzl, E., Heider, S., Majoros, A., Wienerroither, S., Strobl, B., Stockinger, S., Müller, M., Kenner, L., and Decker, T. (2015).
Noncanonical effects of IRF9 in intestinal inflammation: more than type I and type III interferons.
Mol Cell Biol 35: 2332-2343 doi: 10.1128/MCB.01498-14
Wienerroither, S., Shukla, P., Farlik, M., Majoros, A., Stych, B., Vogl, C., Cheon, H., Stark, G.R., Strobl, B., Müller, M., and Decker, T. (2015).
Cooperative transcriptional activation of antimicrobial genes by STAT and NFκB pathways through concerted recruitment of the mediator complex.
Cell Reports 12: 1-13. doi: http://dx.doi.org/10.1016/j.celrep.2015.06.021
Bakiri, L., Macho-Maschler, S., Custic, I., Niemiec, J., Guio-Carrion, A., Hasenfuss, S.C., Eger, A., Müller, M., Beug†, H., and Wagner, E.F. (2015). †1945-2011, SFB member of the 1st funding period; associated with coordination project
Fra-1/AP-1 induces mammary epithelial cell EMT by modulating Zeb1/2 and TGFbeta expression.
Cell Death Differ 22: 336-350. doi: 10.1038/cdd.2014.157
Stiedl, P., McMahon, R., Blaas, L., Stanek, V., Svinka, J., Grabner, B., Zollner, G., Kessler, S.M., Claudel, T., Müller, M., Mikulits§, W., Bilban, M., Esterbauer, H., Eferl§, R., Haybaeck, J., Trauner, M., and Casanova, E. (2015). §SFB member of the 1st and 2nd funding period
Growth hormone resistance exacerbates cholestasis-induced murine liver fibrosis.
Hepatology 61: 613-626. doi: 10.1002/hep.27408
Ustun, S., Lassnig, C., Preitschopf, A., Mikula, M., Müller, M., Hengstschlager, M., and Weichhart, T. (2015).
Effects of the mTOR inhibitor everolimus and the PI3K/mTOR inhibitor NVP-BEZ235 in murine acute lung injury models.
Transplant immunology. [Epub ahead of print] doi: 10.1016/j.trim.2015.06.001
Berry, D., Kuzyk, O., Rauch, I., Heider, S., Schwab, C., Hainzl, E., Decker, T., Müller, M., Strobl, B., Schleper, C., Urich, T., Wagner, M., Kenner, L., and Loy, A. (2015).
Intestinal microbiota signatures associated with inflammation history in mice experiencing recurring colitis
Front Microbiol. 2015; 6: 1408. doi: 10.3389/fmicb.2015.01408
Hainzl, E., Stockinger, S., Rauch, I., Heider, S., Berry, D., Lassnig, C., Schwab, C., Rosebrock, F., Milinovich, G., Schlederer, M., Wagner, M., Schleper, C., Loy, A., Urich, T., Kenner, L., Han, X., Decker, T., Strobl, B., and Muller, M. (2015).
Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis. Journal of immunology 195, 5011-5024.
Journal of immunology 195, 5011-5024
Leitner, N.R., Witalisz-Siepracka, A., Strobl, B., and Muller, M. (2015).
Tyrosine kinase 2 - Surveillant of tumours and bona fide oncogene.
Cytokine 10.1016/j.cyto.2015.10.015
Leopold Wager, C.M., Hole, C.R., Wozniak, K.L., Olszewski, M.A., Mueller, M., and Wormley, F.L., Jr. (2015).
STAT1 Signaling within Macrophages is Required for Anti-fungal Activity against Cryptococcus neoformans.
. Infection and immunity 10.1128/IAI.00935-15.
Shukla, P., Vogl, C., Wallner, B., Rigler, D., Müller, M., and Macho-Maschler, S. (2015).
High-Throughput mRNA and miRNA Profiling of Epithelial-Mesenchymal Transition in MDCK cells.
BMC Genomics 16, 944
Castiglia, V., Piersigilli, A., Ebner, F., Janos, M., Goldmann, O., Dambock, U., Kroger, A., Weiss, S., Knapp, S., Jamieson, A.M., Kirschning, C., Kalinke, U., Strobl, B., Muller, M., Stoiber, D., Lienenklaus, S., and Kovarik, P. (2016).
Type I Interferon Signaling Prevents IL-1beta-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue.
Cell Host Microbe 19, 375-387
Gotthardt, D., Putz, E.M., Grundschober, E., Prchal-Murphy, M., Straka, E., Kudweis, P., Heller, G., Bago-Horvath, Z., Witalisz-Siepracka, A., Cumaraswamy, A.A., Gunning, P.T., Strobl, B., Muller, M., Moriggl, R., Stockmann, C., and Sexl, V. (2016).
STAT5 is a key regulator in NK cells and acts as molecular switch from tumor surveillance to tumor promotion.
Cancer discovery 6, 414-429
Maier, B.B., Hladik, A., Lakovits, K., Korosec, A., Martins, R., Kral, J.B., Mesteri, I., Strobl, B., Muller, M., Kalinke, U., Merad, M., and Knapp, S. (2016).
Type I interferon promotes alveolar epithelial type II cell survival during pulmonary S. pneumoniae infection and sterile lung injury in mice.
European journal of immunology 10.1002/eji.201546201
Majoros, A., Platanitis, E., Szappanos, D., Cheoan, H.J., Vogl, C., Shukla, P., Stark, G.R., Sexl, V., Schreiber, R.D., Schindler, C., Müller, M., and Decker, T. (2016).
Response to interferons and antibacterial innate immunity in absence of tyrosine-phosphorylated STAT1.
EMBO Rep 17, 367-382
Putz, E.M., Majoros, A., Gotthart, D., Prchal-Murphy, M., Zebedin-Brandl, E., Fux, D.A., Schlattl, A., Schreiber, R.D., Carotta, S., Müller, M., Gerner, C., Decker, T., and Sexl, V. (2016).
Novel non-­canonical role of STAT1 in Natural Killer cell cytotoxicity.
OncoImmunology 10.1080/2162402X.2016.1186314.
Zotz, J.S., Wölbing, F., Lassnig, C., Kauffmann, M., Schulte, U., Kolb, A., Whitelaw, B., Müller, M., Biedermann, T., and Huber, M. (2016).
CD13/aminopeptidase N is a negative regulator of mast cell activation.
FASEB J 30, 2225-2235
Linke, M., Pham, H.T., Katholnig, K., Schnoller, T., Miller, A., Demel, F., Schutz, B., Rosner, M., Kovacic, B., Sukhbaatar, N., Niederreiter, B., Bluml, S., Kuess, P., Sexl, V., Muller, M., Mikula, M., Weckwerth, W., Haschemi, A., Susani, M., Hengstschlager, M., Gambello, M.J., and Weichhart, T. (2017).
Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression.
Nat Immunol 10.1038/ni.3655
Majoros, A., Platanitis, E., Kernbauer-Holzl, E., Rosebrock, F., Muller, M., and Decker, T. (2017).
Canonical and Non-Canonical Aspects of JAK-STAT Signaling: Lessons from Interferons for Cytokine Responses.
Front Immunol 8, 29
Crncec, I., Modak, M., Gordziel, C., Svinka, J., Scharf, I., Moritsch, S., Pathria, P., Schlederer, M., Kenner, L., Timelthaler, G., Muller, M., Strobl, B., Casanova, E., Bayer, E., Mohr, T., Stockl, J., Friedrich, K., and Eferl, R. (2018).
Stat1 is a sex-specific tumor suppressor in colitis-associated colorectal cancer.
Mol Oncol 10.1002/1878-0261.12178
Pham, H.T.T., Maurer, B., Prchal-Murphy, M., Grausenburger, R., Grundschober, E., Javaheri, T., Nivarthi, H., Boersma, A., Kolbe, T., Elabd, M., Halbritter, F., Pencik, J., Kazemi, Z., Grebien, F., Hengstschlager, M., Kenner, L., Kubicek, S., Farlik, M., Bock, C., Valent, P., Muller, M., Rulicke, T., Sexl, V., and Moriggl, R. (2018).
STAT5BN642H is a driver mutation for T cell neoplasia.
J Clin Invest 128, 387-401

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