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A10 - The role of the different LUBAC components in TNF-induced cell death, inflammation, immunity and disease

Nieves Peltzer

Department of Translational Genomics, University of Cologne

Contact: m.peltzerSpamProtectionuni-koeln.de
For more information visit: Peltzer lab

Henning Walczak

Department of Biochemistry I, CECAD, University of Cologne

Contact: h.walczakSpamProtectionuni-koeln.de
For more information visit: Walczak lab

Abstract

Receptor-ligand-mediated signalling in cell death, inflammation and immunity is regulated by a fine-tuned system of post-translational modifications by phosphorylation, ubiquitination and their respective reversals. The linear ubiquitin chain assembly complex (LUBAC) modulates signalling via the tumour necrosis factor (TNF) – TNF receptor 1 (TNFR1) system. We found LUBAC and the linear ubiquitin chains it creates to be crucial for the different TNFR1 signalling outputs by enabling full gene activation and preventing cell death. These studies contributed to establishing cell death as a trigger of inflammation and inflammatory disease. In this project we aim to understand and further dissect the biochemistry and function of LUBAC and and its individual components in physiology and in various disease settings. 

Project related Publications

Peltzer, N., Darding, M., Montinaro, A., Draber, P., Draberova, H., Kupka, S., Rieser, E., Fisher, A., Hutchinson, C., Taraborrelli, L., Hartwig, T., Lafont, E., Haas, T.L., Shimizu, Y., Böiers, C., Sarr, A., Rickard, J., Alvarez-Diaz, S., Ashworth, M.T., Beal, A., Enver, T., Bertin, J., Kaiser, W., Strasser, A., Silke, J., Bouillet, P., and Walczak, H. (2018). LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis. Nature 557, 112-117.

Taraborrelli, L.*, Peltzer, N.*, Montinaro, A., Kupka, S., Rieser, E., Hartwig, T., Sarr, A., Darding, D., Draber, P., Haas, T.L., Akarca, A., Marafioti, T., Pasparakis, M., Bertin, J., Gough, P.J., Bouillet, P., Strasser, A., Leverkus, M., Silke, S., and Walczak, H. (2018). LUBAC prevents lethal dermatitis by combined inhibition of TNF-, TRAIL- and CD95L-mediated cell death. Nat Commun 9, 3910. *Equal contribution.

Lafont, E., Draber, P., Rieser, E., Reichert, M., Kupka, S., de Miguel, D., Draberova, H., von Mässenhausen, A., Bhamra, A., Henderson, S., Wojdyla, K., Chalk, A., Surinova, S., Linkermann, A., and Walczak, H. (2018). TBK1 and IKKe prevent TNF-induced cell death by RIPK1 phosphorylation. Nat Cell Biol. 20, 1389-1399.

Zinngrebe, J., Rieser, E., Taraborrelli, L., Peltzer, N., Hartwig, T., Ren, H., Kovács, I., Endres, C., Draber, P., Darding, M., Karstedt, S., Lemke, J., Dome, B., Bergmann, M., Ferguson, B., and Walczak, H. (2016). LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation. J Exp Med 213: 2671-2689.

Kupka, S., De Miguel, D., Draber, P., Martino, L., Surinova, S., Rittinger, K., and Walczak, H. (2016). SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes. Cell Rep 16, 2271-2280.

Draber, P., Kupka, S., Reichert, M., Draberova, H., Lafont, E., Miguel, D., Spilgies, L., Surinova, S., Taraborrelli, L., Hartwig, T., Rieser, E., Martino, L., Rittinger, K., and Walczak, H. (2015) LUBAC-recruited CYLD and A20 restrict gene activation and regulate cell death by exerting opposing effects on linear ubiquitin in signaling complexes. Cell Rep 13, 2258-2272.

Peltzer, N., Rieser, E., Taraborrelli, L., Draber, P., Darding, M., Pernaute, B., Shimizu, Y., Daboh, A., Draberova, H., Montinaro, A., Martinez-Barbera, J.P., Silke, J., Rodriguez, T.A., and Walczak, H. (2014). HOIP deficiency caused embryonic lethality by aberrant TNFR1-mediated endothelial cell death. Cell Rep 9, 153-165.

Gerlach, B., Cordier, S.M., Schmukle, A.C., Emmerich, C.H., Rieser, E., Haas, T.L., Webb, A.I., Rickard, J.A., Anderton, H., Wong, W.W.-L., Nachbur, U., Gangoda, L., Warnken, U., Purcell, A.W., Silke, J., and Walczak, H. (2011). Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591-596.

Bulat, N., Jaccard, E., Peltzer, N., Khalil, H., Yang, J.Y., Dubuis, G., and Widmann, C. (2011). RasGAP-derived fragment N increases the resistance of beta cells towards apoptosis in NOD mice and delays the progression from mild to overt diabetes. PloS One 6, e22609.

Haas, T.L., Emmerich, C.H., Gerlach, B., Schmukle, A.C., Cordier., S.M., Rieser, E., Feltham, R., Vince, J., Warnken, U., Wenger, T., Koschny, R., Komander, D., Silke, J., and Walczak, H. (2009). Recruitment of the linear ubiquitin chain assembly complex (LUBAC) stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell 36, 831-844.

 

Patents

A method for treating diseases by combined inhibition of TNF superfamily members and/or cell death signalling pathways (such as inflammation and inflammation-associated diseases including auto-immune diseases, neuro-inflammatory diseases, neuro-degenerative diseases, ischaemic diseases, sepsis, and cancer)” UCL Business PLC; Filed: 22/01/18, Inventors: Henning Walczak, Lucia Taraborrelli, Nieves Peltzer