UNIVERSITÄT ZU KÖLN

Chen YG, Rieser E, Bhamra A, Surinova S, Kreuzaler P, Ho MH, Tsai WC, Peltzer N, de Miguel D, Walczak H. LUBAC enables tumor-promoting LTβ receptor signaling by activating canonical NF-κB. Cell Death Differ. 2024 Aug 30. doi: 10.1038/s41418-024-01355-w. Epub ahead of print. PMID: 39215104.

Veli Ö, Kaya Ö, Varanda AB, Hildebrandt X, Xiao P, Estornes Y, Poggenberg M, Wang Y, Pasparakis M, Bertrand MJM, Walczak H, Annibaldi A, Cardozo AK, Peltzer N. RIPK1 is dispensable for cell death regulation in β-cells during hyperglycemia. Mol Metab. 2024 Jul 12:101988. doi: 10.1016/j.molmet.2024.101988. Epub ahead of print. PMID: 39004142.

Oda H, Manthiram K, Chavan PP, Rieser E, Veli Ö, Kaya Ö, Rauch C, Nakabo S, Kuehn HS, Swart M, Wang Y, Çelik NI, Molitor A, Ziaee V, Movahedi N, Shahrooei M, Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency. Nat Immunol. 2024 Apr 12. doi: 10.1038/s41590-024-01817-w. Epub ahead of print. PMID: 38609546.

Albert MC, Uranga-Murillo I, Arias M, De Miguel D, Peña N, Montinaro A, Varanda AB, Theobald SJ, Areso I, Saggau J, Koch M, Liccardi G, Peltzer N, Rybniker J, Hurtado-Guerrero R, Merino P, Monzón M, Badiola JJ, Reindl-Schwaighofer R, Sanz-Pamplona R, Cebollada-Solanas A, Megyesfalvi Z, Dome B, Secrier M, Hartmann B, Bergmann M, Pardo J, Walczak H. Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality. Cell Death Differ. 2024 Mar 21. doi: 10.1038/s41418-024-01278-6. Epub ahead of print. PMID: 38514848

Teague, H.C., Lefevre, C., Rieser, E., Wolfram, L., de Miguel, D., Patricio de Oliveira, D., Oliveira, M., Mansur, D.S., Irigoyen, N., Walczak, H. and Ferguson, B.J. (2023) LUBAC is required for RIG-I sensing of RNA viruses. Cell Death Differ. doi: 10.1038/s41418-023-01233-x.

Martinez Lagunas, K., Savcigil, D.P., Zrilic, M., Carvajal Fraile, C., Craxton, A., Self, E., Uranga-Murillo, I., de Miguel, D., Arias, M., Willenborg, S., Piekarek, M., Albert, MC., Nugraha, K., Lisewski, I., Janakova, E., Igual, N., Tonnus, W., Hildebrandt, X., Ibrahim, M., Ballegeer, M., Saelens, X., Kueh, A., Meier, P., Linkermann, A., Pardo, J., Eming, S., Walczak, H., MacFarlane, M., Peltzer, N., Annibaldi, A. (2023) Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair. Sci Adv. doi: 10.1126/sciadv.adg2829

Augustin, M., Heyn, F., Ullrich, S., Sandaradura de Silva, U., Albert, M.C., Linne, V., Schlotz, M., Schommers, P., Pracht, E., Horn, C., Suarez, I., Simonis, A., Picard, L.K., Zoufaly, A., Wenisch, C., Fätkenheuer, G., Gruell, H., Klein, F., Hallek, M., Walczak, H., Rybniker, J., Theobald S.J., and Lehmann C. (2023) Immunological fingerprint in coronavirus disease-19 convalescents with and without post-COVID syndrome. Front Med (Lausanne). 10, 1129288. doi: 10.3389/fmed.2023.1129288

Di Benedetto, C., Khan, T., Serrano-Saenz, S., Rodriguez-Lemus, A., Klomsiri, C., Beutel, T.-M., Thach, A., Walczak, H., and Betancur, P. (2023). Enhancer Clusters Drive Type I Interferon-Induced TRAIL Overexpression in Cancer, and Its Intracellular Protein Accumulation Fails to Induce Apoptosis. Cancers 15, 967. https://doi.org/10.3390/cancers15030967

Montinaro, A. & Walczak, H. (2022) Harnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01059-z (review)

Hildebrandt, X., Ibrahim, M. & Peltzer, N. Cell death and inflammation during obesity: “Know my methods, WAT(son)”. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01062-4 (review)

Theobald, S.J., Simonis, A., Mudler, J.M., Göbel, U., Acton, R., Kohlhas, V., Albert, M.-C., Hellmann, A.-M., Malin, J.J., Winter, S., Hallek, M., Walczak, H., Nguyen, P.-H., Koch, M., Rybniker, J. (2022) Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination. EMBO Mol Med e15888 https://doi.org/10.15252/emmm.202215888

Peltzer, N., & Annibaldi, A., (2022) Cell Death-Related Ubiquitin Modifications in Inflammatory Syndromes: From Mice to Men. Biomedicines 10(6): 1436 doi: 10.3390/biomedicines10061436 (review)

Li, X., Huang, C.-H., Sánchez-Rivera, F.J., Kennedy, M.C., Tschaharganeh, D.F., Morris IV, J.P., Montinaro, A., O'Rourke, K.P., Banito, A, Wilkinson, J.E., Chen, C.-C., Ho, Y.-J., Dow, L.E., Tian, S., Luan, W., de Stanchina, E., Zhang, T., Gray, N.S., Walczak, H., Lowe, S.W. (2022) A preclinical platform for assessing antitumor effects andsystemic toxicities of cancer drug targets. PNAS 2022 Vol. 119 No. 17 e2110557119 https://doi.org/10.1073/pnas.2110557119

Peltzer, N. (2022) Linear ubiquitin as a common regulator of cellular stress. FEBS Journal 2022 https://doi.org/10.1111/febs.16425 (review)

Montinaro, A., Areso Zubiaur, I., Saggau, J., Kretz, A-L-, Ferreira, R.M.M., Hassan, O., Kitzig, E., Müller, I., El-Bahrawy, M.A., von Karstedt, S., Kulms, D., Liccardi, G., Lemke J. & Walczak, H. (2021) Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers. Cell Death Differentiation. https://doi.org/10.1038/s41418-021-00869-x

Jain, R., Zhao, K., Sheridan, J.M. Heinlein, M., Kupresanin, F., Abeysekera, W., Hall, C., Rickard, J., Bouillet, P., Walczak, H., Strasser, A., Silke, J. & Gray, D.H.D. (2021). Dual roles for LUBAC signaling in thymic epithelial cell development and survival. Cell Death & Differentiation.

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

Former Participating project Leader:

Henning Walczak

Department of Biochemistry I, CECAD, University of Cologne
Contact: h.walczak(at)uni-koeln.de
For more information visit: Walczak lab

Former 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.