A03 - Hornung

A03 - The role of metalloprotease activity in necroptosis driven inflammation

Veit Hornung

Gene Center Munich, Department for Biochemistry, Ludwig-Maximilians-University Munich
Contact: hornung(at)genzentrum.lmu.de
For more information visit: Hornung lab

Abstract

Unlike apoptosis, necroptosis results in the release of cytosolic contents that are believed to induce inflammation. Using a well-established in vitro model of human cells, this project aims to characterise necroptosis-driven inflammation in vitro and to identify necroptosis-dependent DAMP or alarmin molecules. By systematically perturbing all known PRR- and cytokine receptor-dependent signalling cascades within bystander cells this project will additionally characterise the dominant sensing modalities in this setting. These efforts will provide novel mechanistic insights into how necroptosis triggers inflammation.

Recent Publications

2024

Hornung V, Gaidt MM. Friendly fire: recognition of self by the innate immune system. Curr Opin Immunol. 2024 Oct;90:102457. doi: 10.1016/j.coi.2024.102457. Epub 2024 Sep 3. PMID: 39232338.

Szymanska I, Bauernfried S, Komar T, Hornung V. Vaccinia virus F1L blocks the ribotoxic stress response to subvert ZAKα-dependent NLRP1 inflammasome activation. Eur J Immunol. 2024 Jul 31:e2451135. doi: 10.1002/eji.202451135. Epub ahead of print. PMID: 39086059.

Wang M, Flaswinkel H, Joshi A, Napoli M, Masgrau-Alsina S, Kamper JM, Henne A, Heinz A, Berouti M, Schmacke NA, Hiller K, Kremmer E, Wefers B, Wurst W, Sperandio M, Ruland J, Fröhlich T, Hornung V. Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation. Nat Commun. 2024 Jul 31;15(1):6438. doi: 10.1038/s41467-024-50104-7. PMID: 39085210; PMCID: PMC11291651.

Sun Z, Hornung V. A critical role for palmitoylation in pyroptosis. Mol Cell. 2024 Jun 20;84(12):2218-2220. doi: 10.1016/j.molcel.2024.05.023. PMID: 38906113. (Review)

Project A03 Publications 1st Funding Period 2020 - 2023

2022

Sun, Z., Cernilogar, F.M., Horvatic, H., Yeroslaviz, A., Abdullah, Z., Schotta, G. and Hornung. V. (2023) β1 integrin signaling governs necroptosis via the chromatin-remodeling factor CHD4. Cell Rep. 42, 113322. doi: 10.1016/j.celrep.2023.113322. Epub ahead of print. PMID: 37883227.

Pinci, F., Gaidt, M.M., Jung, C., Nagl, D., Kuut, G., Hornung, V. (2022) Tumor necrosis factor is a necroptosis-associated alarmin. Front. Immunol. 13:1074440. doi: 10.3389/fimmu.2022.1074440

Schmacke, N.A., O'Duill, F., Gaidt, M.M., Szymanska, I., Kamper, J.M., Schmid-Burgk, J.L., Mädler, S.C., Mackens-Kiani, T., Kozaki, T., Chauhan, D., Nagl, D., Stafford, C.A., Harz, H., Fröhlich, A.L.. Pinci, F., Ginhoux, F.L., Beckmann, R., Mann, M., Leonhardt, H., Hornung, V. (2022) IKKβ primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network. Immunity 2022 Nov 9;S1074-7613(22)00562-3. doi: 10.1016/j.immuni.2022.10.021.

Stafford, C.A., Gassauer, A.-M., de Oliveira Mann, C.C., Tanzer, M.C., Fessler, E., Wefers, B., Nagl, D., Kuut, G., Sulek, K., Vasilopoulou, C., Schwojer, S.J., Wiest, A., Pfautsch, M.K., Wurst, W., Yabal, M., Fröhlich, T., Mann, M., Gisch, N., Jae, L.T., & Hornung, V. Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation. Nature 609, 590–596 (2022). https://doi.org/10.1038/s41586-022-05125-x

2021

2020

Project related Publications

2008 - 2019

Chauhan, D., Bartok, E., Gaidt, M.M., Bock, F.J., Herrmann, J., Seeger, J.M., Broz, P., Beckmann, R., Kashkar, H., Tait, S.W.G., ... and Hornung, V. (2018). BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1beta Maturation in Macrophages. Cell Rep 25, 2354-2368 e2355.

Gaidt, M.M., Ebert, T.S., Chauhan, D., Ramshorn, K., Pinci, F., Zuber, S., O'Duill, F., Schmid-Burgk, J.L., Hoss, F., Buhmann, R., ... and Hornung, V. (2017). The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3. Cell 171, 1110-1124 e1118.

Gaidt, M.M., Ebert, T.S., Chauhan, D., Schmidt, T., Schmid-Burgk, J.L., Rapino, F., Robertson, A.A., Cooper, M.A., Graf, T., and Hornung, V. (2016). Human Monocytes Engage an Alternative Inflammasome Pathway. Immunity 44, 833-846.

Gaidt, M.M., Rapino, F., Graf, T., and Hornung, V. (2018). Modeling Primary Human Monocytes with the Trans-Differentiation Cell Line BLaER1. Methods in molecular biology (Clifton, NJ) 1714, 57-66.

Hornung, V., Ablasser, A., Charrel-Dennis, M., Bauernfeind, F., Horvath, G., Caffrey, D.R., Latz, E., and Fitzgerald, K.A. (2009). AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514-518.

Hornung, V., Bauernfeind, F., Halle, A., Samstad, E.O., Kono, H., Rock, K.L., Fitzgerald, K.A., and Latz, E. (2008). Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature immunol 9, 847-856.

Lehle, A.S., Farin, H.F., Marquardt, B., Michels, B.E., Magg, T., Li, Y., Liu, Y., Ghalandary, M., Lammens, K., Hollizeck, S., ... Hornung, V., et al. (2019). Intestinal Inflammation and Dysregulated Immunity in Patients With Inherited Caspase-8 Deficiency. Gastroenterology 156, 275-278.

Li, Y., Fuhrer, M., Bahrami, E., Socha, P., Klaudel-Dreszler, M., Bouzidi, A., Liu, Y., Lehle, A.S., Magg, T., Hollizeck, S., ... Hornung, V., et al. (2019). Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proc Natl Acad Sci U S A 116, 970-975.

Paludan, S.R., Reinert, L.S., and Hornung, V. (2019). DNA-stimulated cell death: implications for host defence, inflammatory diseases and cancer. Nat Rev Immunol 19, 141-153.

van den Boorn, J.G., Jakobs, C., Hagen, C., Renn, M., Luiten, R.M., Melief, C.J., Tuting, T., Garbi, N., Hartmann, G., and Hornung, V. (2016). Inflammasome-Dependent Induction of Adaptive NK Cell Memory. Immunity 44, 1406-1421.

UNIVERSITÄT ZU KÖLN

Sonderforschungsbereich 1403