SFB796 - Sub project B9


Viral regulators of the cellular ripoptosome protein complex


Project summary

With the recent discovery of necroptosis as a form of programmed necrosis, our view on how cell death is regulated has changed and many recent studies on apoptosis are currently revisited in light of these discoveries. It is becoming increasingly clear, that necroptosis is tightly regulated by a cellular protein platform denoted ripoptosome involving the two cellular kinases RIP1 and RIP3. An important observation has been that cFLIP is a central regulator of cell death in the ripoptosome. cFLIP not only regulates cell survival versus apoptosis, the short isoform of cFLIP (cFLIPShort) can induce necroptosis. Interestingly, certain herpesviruses and poxviruses including the Kaposi sarcoma-associated herpesvirus (KSHV) express a protein that shares structural similarities to cFLIPShort. It is therefore tempting to speculate, that viral FLIPs (vFLIPs) like their cellular counterparts may regulate the ripoptosome and therefore may reprogram cell death.

In this project we seek to prove this hypothesis and will investigate whether vFLIP mediated ripoptosome-regulation influences viral replication and organ pathogenesis. Accordingly, we will determine the role of KSHV-vFLIP on necroptosis and ripoptosome formation in different in vitro overexpression systems and on the viral life cycle in infected cells. We will furthermore investigate the role of KSHV-vFLIP on tissue homeostasis in gut and liver using conditional mouse model systems. Finally, we will validate the impact of the results obtained above at the clinical level using serologic analyses and expression studies in KS, inflammatory bowel disease and colorectal cancer.


Project relevant publications

  • Britzen-Laurent, N., C. Herrmann, E. Naschberger, R.S. Croner & M. Stürzl.   Pathophysiological role of guanylate binding proteins in gastrointestinal diseases.   World Journal of Gastroenterology   [in press].

  • Mahapatro, M., G.-W. He, E. Giner-Ventura, T. Mchedlidze, M. Kindermann, S. Vetrano, S. Danese, C. Günther, M. F. Neurath, S. Wirtz, C. Becker.   (2016).   Programming of intestinal epithelial differentiation by IL-33 derived from pericryptal fibroblasts in response to systemic infection.   Cell Rep.   15(8): 1743-56.

  • Leppkes M., M.F. Neurath, M. Herrmann, C. Becker.   (2016).   Immune deficiency versus immune excess in Inflammatory Bowel Diseases - STAT3 as a rheo-STAT of intestinal homeostasis.   Leukoc Biol.   99(1): 57-66.

  • Martini E., N. Wittkopf, C. Günther, H. Okada, A. Watson, E. Podstawa, I. Backert, M.F. Neurath, C. Becker.   (2016).   Loss of Survivin in intestinal epithelial progenitor cells leads to mitotic catastrophe and breakdown of gut immune homeostasis.   Cell Rep.   14(5): 1062-73.

  • Roulis M., G. Bongers, M. Armaka, T. Salviano, Z. He, A. Singh, U. Seidler, C. Becker, J. Demengeot, G. Furtado, S.A. Lira, G. Kollias.   (2016).   Host and microbiota interactions are critical for development of murine Crohn's-like ileitis.   Mucosal Immunology   9(3): 787-97.

  • Murtadak V, Becker C, Stürzl M.   (2015).   Cell death inhibition by KSHV.   Aging-US   7: 750-1.

  • Feiersinger, F., E. Nolte, S. Wach, T.T. Rau, N. Vassos, C. Geppert, A. Konrad, S. Merkel, H. Taubert, M. Stürzl & R.S. Croner   (2016).   MiRNA-21 expression decreases from primary tumors to liver metastases in colorectal carcinoma.   PLoS One   11, e0148580.

  • Haep L., N. Britzen-Laurent, T.G. Weber, E. Naschberger, A. Schaefer, E. Kremmer, S. Foersch, M. Vieth, W. Scheuer, S. Wirtz, M. Waldner & M. Stürzl   (2015).   Interferon gamma counteracts the angiogenic switch and induces vascular permeability in dextran sulfate sodium colitis in mice.   Inflammatory Bowel Diseases   21, 2360-71.

  • Chudasama P, Konrad A, Jochmann R, Lausen B, Holz P, Naschberger E, Neipel F, Britzen-Laurent N, Stürzl M   (2015).   Structural proteins of Kaposi's sarcoma-associated herpesvirus antagonize p53-mediated apoptosis.   Oncogene   34: 639-49.

  • Günther C, Buchen B, He G, Hornef M, Torow N, Neumann H, Wittkopf N, Martini E, Basic M, Bleich A, Watson AJ, Neurath MF, Becker C   (2015).   Caspase-8 controls the gut response to microbial challenges by TNFalpha -dependent and -independent pathways.   Gut   64(4): 601-610.

  • Wu JJ, Li W, Shao Y, Avey D, Fu B, Gillen J, Hand T, Ma S, Liu X, Miley W, Konrad A, Neipel F, Stürzl M, Whitby D, Li H, Zhu F   (2015).   Inhibition of cGAS DNA sensing by a herpesvirus virion protein.   Cell Host Microbe   18: 333-44.

  • Becker C., M.F. Neurath, S. Wirtz.   (2015).   The intestinal microbiota in inflammatory bowel disease.   ILAR J.   56(2): 192-204.

  • Wittkopf N., G. Pickert, U. Billmeier, M. Mahapatro, S. Wirtz, E. Martini, M. Leppkes, M.F. Neurath, C. Becker.   (2015).   Activation of intestinal epithelial Stat3 orchestrates tissue defense during gastrointestinal infection.   PLOS one   10(3): e0118401.

  • Kreiser S., J. Eckhardt, C. Kuhnt, M. Stein, L. Krzyzak, C. Staab, C. Tucher, I. Knippertz, C. Becker, C. Günther, A. Steinkasserer, M. Lechmann.   (2015).   Murine CD83-positive T cells mediate regulatory T cell-like suppressor functions in vitro and in vivo.   Immunobiology   220(2): 270-9.

  • Hävemeier A, Gramolelli S, Pietrek M, Jochmann R, Stürzl M, Schulz TF   (2014).   Activation of NF-κB by the Kaposi's sarcoma herpesvirus K15 protein involves recruitment of the NF-κB-inducing kinase, IκB kinases and phosphorylation of p65.   J Virol   88: 13161-72.

  • Full F, Jungnickl D, Reuter N, Bogner E, Brulois K, Scholz B, Stürzl M, Myoung J, Jung JU, Stamminger T, Ensser A   (2014).   Kaposi's sarcoma associated herpesvirus tegument protein ORF75 is essential for viral lytic replication and plays a critical role in the antagonization of ND10-instituted intrinsic immunity.   PLoS Pathogens   10: e1003863.

  • Jochmann, R., P. Holz, H. Sticht & M. Stürzl.   (2014).   Validation of the reliability of computational O-GlcNAc prediction.   Biochim Biophys Acta   1844, 416-21.

  • Ostler, N., N. Britzen-Laurent, A. Liebl, E. Naschberger, G. Lochnit, M. Ostler, F. Forster, P. Kunzelmann, S. Ince, V. Supper, G.J.K. Praefcke, D.W. Schubert, H. Stockinger, C. Herrmann & M. Stürzl.   (2014).   IFN-γ-induced guanylate binding protein-1 is a novel actin cytoskeleton remodeling factor.   Mol Cell Biol   34, 196-209.

  • Ostler, N., N. Britzen-Laurent, A. Liebl, E. Naschberger, G. Lochnit, M. Ostler, F. Forster, P. Kunzelmann, S. Ince, V. Supper, G.J.K. Praefcke, D.W. Schubert, H. Stockinger, C. Herrmann & M. Stürzl.   (2014).   COVER FIGURE.   Mol Cell Biol.

  • Takahashi N, Vereecke L, Bertrand MJM, Duprez L, Berger SB, Divert T, Goncalves A, Sze M, Gilbert B, Kourula S, Goossens V, Lefevre S, Günther C, Becker C, Bertin J, Gough PJ, Declercq W, van Loo G, Vandenabeele P   (2014).   RIPK1 is a guardian of intestinal homeostasis protecting the epithelium against apoptosis.   Nature   513(7516): 95-9.

  • Günther, C., B. Buchen, M.F. Neurath, Becker C.   (2014).   Regulation and pathophysiological role of epithelial turnover in the gut.   Semin Cell Dev Biol.   S1084-9521(14): 177-3.

  • Leppkes M., Roulis, M. M.F. Neurath, Kollias, G., Becker C.   (2014).   The pleiotropic functions of TNF-alpha in the regulation of the intestinal epithelial response to inflammation.   Int Immunol.   26(9): 509-515.

  • Wittkopf N., M.F. Neurath, Becker C.   (2014).   Immune-epithelial crosstalk at the intestinal surface.   J Gastroenterol.   49(3): 375-87.

  • Eckhardt J., S. Kreiser, M. Döbbeler, C. Nicolette, M.A. DeBenedette, I.Y. Tcherepanova, C. Ostalecki, A.J. Pommer, C. Becker, C. Günther, E. Zinser, T.W. Mak, A. Steinkasserer.   (2014).   Soluble CD83 Ameliorates Experimental Colitis in Mice.   Mucosal Immunology   7(4): 1006-18.

  • Grenz, S., E. Naschberger, N. Britzen-Laurent, U. Schaal, S. Merkel, A. Konrad, M. Aigner, T.T. Rau, A. Hartmann, R.S. Croner, W. Hohenberger & M. Stürzl.   (2013).   IFN-gamma-driven intratumoral microenvironment exhibits superior prognostic effect as compared to an IFN-alpha-driven microenvironment in patients with colon carcinoma.   Am J Pathol   183, 1897-909.

  • Wittkopf N, Günther C, Martini E, He G, Amann K, He Y-W, Schuchmann M, Neurath MF, Becker C   (2013).   Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating Caspase-8.   Gastroenterology   145(6):1369-79.

  • Becker C, Watson AJ, Neurath MF   (2013).   The intricate role of caspases in the pathogenesis of inflammatory bowel disease.   Gastroenterology   144(2): 283-93.

  • Günther C, Neumann H, Neurath MF, Becker C   (2013).   Apoptosis, necrosis and necroptosis: Cell death regulation in the intestinal epithelium.   Gut   62(7): 1062-71.

  • Hahn A, Kaufmann JK, Wies E, Naschberger E, Panteleev-Ivlev J, Schmidt K, Holzer A, Schmidt M, Chen J, König S, Ensser A, Myoung J, Brockmeyer NH, Stürzl M, Fleckenstein B, Neipel F.   (2012).   The Ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma-associated herpesvirus.   Nature Med.   [In press]   doi: 10.1038/nm.2805

  • Kuhn E, Naschberger E, Konrad A, Croner RS, Britzen-Laurent N, Jochmann R, Münstedt H, Stürzl M.   (2012).   A novel chip-based parallel transfection assay to evaluate paracrine cell interactions.   Lab on a Chip   12(7):1363-72

  • Wittkopf, N, Günther C, Martini E, Waldner M, Neurath MF, Becker C.   (2012).   Lack of intestinal epithelial Atg7 affects Paneth cell granule formation but does not compromise immune homeostasis in the gut.   Clin Dev Immunol.   doi:10.1155/2012/278059

  • Günther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF, Becker C.   (2011).   Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis.   Nature   477(7364):335-9

  • Chalaris A, Adam N, Sina C, Rosenstiel P, Lehmann J, Schirmacher P, Hartmann D, Cichy J, Gawrilova O, Schreiber S, Jostock T, Mathews V, Hässler R, Becker C, Neurath MF, Reiss K, Saftig P, Scheller J, Rose-John S.   (2010).   Inflammation and Regeneration are orchestrated by the Disintegrin Metalloprotease Adam17.   J. Exp. Med.   207(8):1617-24