Transcriptional networking of STAT1 isoforms
NETWORK CONTRIBUTION
Most STAT proteins exist as a full-length α-isoform and a β-isoform that lacks the C-terminal transactivation domain (TAD). Although it is established that the β-isoforms are transcriptionally active, their mechanism of action and specificity are unclear. We will investigate the role of the individual STAT1 isoforms in different layers of gene regulation, including the establishment/activation of enhancers, networking with other TFs, interaction with co-factors and recruitment of the basal transcriptional machinery. The work will be performed in bone marrow-derived macrophages (under basal conditions and in response to IFNγ).
Our major goal is to evaluate the functional consequences on gene expression when naïve CD4+ T cells are activated, building on the finding that STAT1 isoforms are subject to a unique regulation in T cells.
Within the proposed project we investigate STAT1 isoform-specific TF and chromatin regulatory functions.
CONTACT
Department of Biomedical Sciences, Institute of Animal Breeding and Genetics
University of Veterinary Medicine Vienna, Vetmeduni Vienna
A-1210 Vienna
Austria
PUBLICATIONS
SFB-F61 / F28 related publications - Group Strobl
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Derecka, M., Gornicka, A., Koralov, S.B., Szczepanek, K., Morgan, M., Raje, V., Sisler, J., Zhang, Q., Otero, D., Cichy, J., Rajewsky, K., Shimoda, K., Poli, V., Strobl, B., Pellegini, S., Harris, T.E., Seale, P., Russell, A.P., McAinch, A.J., O'Brien, P.E., Keller, S., Croniger, C.M., Kordula, T., and Larner, A.C. (2012). Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity. Cell Metab 16: 814-824. doi: 10.1016/j.cmet.2012.11.005 |
| 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 |
| 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 |
| 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 |
| 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 |
| Strobl, B., and Moriggl, R. (2014). Editorial: Recovery from chemotherapy depends on STAT1 for replenishment of B lymphopoiesis. J Leukocyte Biol 95: 849-851. [editorial review] doi: 10.1189/jlb.0114051 |
| 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 |
| 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 |
| Wiesauer, I., Gaumannmuller, C., Steinparzer, I., Strobl, B., and Kovarik§, P. (2015). §SFB member of the 1st funding period Promoter occupancy of STAT1 in interferon responses is regulated by processive transcription. Mol Cell Biol 35: 716-727. doi: 10.1128/MCB.01097-14 |
| Bauer, E., Witalisz, A., Strobl, B., and Stoiber, D. (2015). Methods to study tumor surveillance using tumor cell transplantation into genetically engineered mice. Methods Mol Biol 1267: 439-456. [review] doi: 10.1007/978-1-4939-2297-0_22 |
| Karjalainen, A., Shoebridge, S., Krunic, M., Simonovic, N., Tebb, G., Macho-Maschler, S., Strobl, B. and Müller, M. TYK2 in Tumor Immunosurveillance Cancers (Basel). 2020 Jan 8; 12 (1):E150. 10.3390/cancers12010150 |
| Gracey, E., Hromadova, D., Lim, M., Qaiyum, Z., Zeng, M., Yao, Y., Srinath, A., Baglaenko, Y., Yeremenko, N., Westlin, W., Masse, C., Muller, M., Strobl, B., Miao, W. and Inman, R. D. TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis J Clin Invest. 2020 Mar 9. pii: 126567. doi: 10.1172/JCI126567 |
| Roewe, J., Stavrides, G., Strueve, M., Sharma, A., Marini, F., Mann, A., Smith, S.A., Kaya, Z., Strobl, B., Mueller, M., Reinhardt, C., Morrissey, J.H., and Bosmann, M. Bacterial polyphosphates interfere with the innate host defense to infection Nat Commun 11, 4035. Doi: 10.1038/s41467-020-17639-x |
| Pflügler, S., Svinka, J., Scharf, I., Crncec, I., Filipits, M., Charoentong, P., Tschurtschenthaler, M., Kenner, L., Awad, M., Stift, J., Schernthanner, M., Bischl, R., Herndler-Brandstetter, D., Glitzner, E., Moll, H.P., Casanova, E., Timelthaler, G., Sibilia, M., Gnant, M., Lax, S., Thaler, J., Müller, M., Strobl, B., Mohr, T., Kaser, A., Trajanoski, Z., Heller, G., and Eferl, R. IDO1+ Paneth cells promote immune escape of colorectal cancer Commun Biol 3, 252. Doi: 10.1038/s42003-020-0989-y |
| Meissl, K., Simonovic, N., Amenitsch, L., Witalisz-Siepracka, A., Klein, K., Lassnig, C., Puga, A., Vogl, C., Poelzl, A., Bosmann, M., Dohnal, A., Sexl, V., Müller, M., and Strobl, B. STAT1 isoforms differentially regulate NK cell maturation and anti-tumour activity Front Immunol 11, 2189. Doi: 10.3389/fimmu.2020.02189 |
| Pezoldt, J., Wiechers, C., Erhard, F., Rand, U., Bulat, T., Beckstette, M., Brendolan, A., Huehn, J., Kalinke, U., Mueller, M., Strobl, B., Deplancke, B., Čičin-Šain, L., and Sitnik, K.M. Single-cell transcriptional profiling of splenic fibroblasts reveals subset-specific innate immune signatures in homeostasis and during viral infection Commun Biol 2021 Dec 4, 1355. doi: 10.1038/s42003-021-02882-9 |
| De Vries, L. C. S., Ghiboub, M., van Hamersveld, P. H. P., Welting, O., Verseijden, C., Bell, M. J., Rioja, I., Prinjha, R. K., Koelink, P. J., Strobl, B., Müller, M., D'Haens, G. R., Wildenberg, M. E., and De Jonge, W.J. Tyrosine Kinase 2 signalling drives pathogenic T-cells in colitis J Crohns Colitis 2021 Apr 15, 617-630. doi: 10.1093/ecco-jcc/jjaa199 |
| Watzenboeck, M.L., Drobits, B., Zahalka, S., Gorki, A.D., Farhat, A., Quattrone, F., Hladik, A., Lakovits, K., Richard, G.M., Lederer, T., Strobl, B., Versteeg, G.A., Boon, L., Starkl, P., and Knapp, S. Lipocalin 2 modulates dendritic cell activity and shapes immunity to influenza in a microbiome dependent manner PLoS Pathog 17, e1009487. Doi: 10.1371/journal.ppat.1009487 |
| Schroeder, J.H., Roberts, L.B., Meissl, K., Lo, J.W., Hromadová, D., Hayes, K., Zabinski, T., Read, E., Moreira Heliodoro, C., Reis, R., Howard, J.K., Grencis, R.K., Neves, J.F., Strobl, B., and Lord, G.M. Sustained Post-Developmental T-Bet Expression Is Critical for the Maintenance of Type One Innate Lymphoid Cells In Vivo Front Immunol 12, 760198. Doi: 10.3389/fimmu.2021.760198 |
| Schroeder, J.-H., Meissl, K., Hromadová, D., Lo, J.W., Neves, J.F., Howard, J.K., Helmby, H., Powell, N., Strobl, B., and Lord, G.M. T-Bet Controls Cellularity of Intestinal Group 3 Innate Lymphoid Cells Front Immunol 11, 623324. Doi: 10.3389/fimmu.2020.623324 |
| Schnepf, D., Crotta, S., Thamamongood, T., Stanifer, M., Polcik, L., Ohnemus, A., Vier, J., Jakob, C., Llorian, M., Gad, H.H., Hartmann, R., Strobl, B., Kirschnek, S., Boulant, S., Schwemmle, M., Wack, A., and Staeheli, P. Selective Janus kinase inhibition preserves interferon-λ-mediated antiviral responses Sci Immunol 6, eabd5318. Doi: 10.1126/sciimmunol.abd5318 |
| Woess, K., Macho-Maschler, S., Van Ingen Schenau, D.S., Butler, M., Lassnig, C., Valcanover, D., Poelzl, A., Meissl, K., Maurer, B., Brandstoetter, T., Vogl, C., Koren, A., Kubicek, S., Orlova, A., Moriggl, R., Strobl, B., Sexl, V., Van Leeuwen, F.N., Kuiper, R.P., and Mueller, M. Oncogenic TYK2(P760L) kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade Haematologica 2022 Jan 13. doi: 10.3324/haematol.2021.279848 |
