Pasparakis, Manolis - B 09
Role of autophagy in the regulation of ZBP1-mediated cell death and inflammation
Prof. Dr. Manolis Pasparakis
Institute for Genetics - CECAD
CMMC - PI - B 09
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Institute for Genetics - CECAD
Joseph-Stelzmann-Str. 26
50931 Cologne
Introduction
Our previous work showed that ZBP1 is activated by sensing endogenous Z-RNA derived from endogenous retroelements (EREs) and induces RIPK3-MLKL-necroptosis resulting in chronic inflammation in the skin and intestine of mice with epithelial cell-specific inhibition of RIPK1 or FADD-Caspase-8 signalling3. More recently, we showed that ZBP1 promotes fatal type I IFN responses in mice with hemizygous expression of ADAR1 with mutated Z domain in a manner independent of RIPK3-MLKL-dependent necroptosis and FADD-Caspase-8-dependent apoptosis as well as RHIM-dependent RIPK1 signalling 5. These results revealed new and important functions of ZBP1, acting as a sensor of ERE-derived Z-RNA to promote pathogenic cell death, inflammatory and IFN responses in relevant mouse models, suggesting that ZBP1 may play an important role in the pathogenesis of human diseases. Therefore, understanding the mechanisms regulating ZBP1 activation may have important therapeutic implications for the treatment of human diseases.
In this proposal, we aim to study the role of autophagy in the regulation of ZBP1-mediated signalling to cell death and inflammation. We will use in vivo genetic approaches in combination with in vitro cellular, molecular and biochemical assays to assess how autophagy impacts on ZBP1 activation and downstream signalling. Specifically, we will study how inhibition of autophagy affects ZBP1 cell death and inflammation in genetic mouse models and will experimentally assess the role of autophagy in regulating ZBP1 either directly by regulating its protein levels, or indirectly by clearing damaged mitochondria and preventing the accumulation of cytosolic mtDNA and/or RNA. These studies will shed light on the mechanisms regulating ZBP1 activation and may reveal novel therapeutic targets for ZBP1-mediated inflammatory diseases.
Lab Website
For more information about the research, please check Manolis Pasparakis Lab.
Affiliations
Publications generated during 1/2023-12/2025 with CMMC affiliation
2024 (up to June)
- Eren RO, Kaya GG, Schwarzer R, and Pasparakis M (2024). IKKepsilon and TBK1 prevent RIPK1 dependent and independent inflammation. Nat Commun15, 130. doi:10.1038/s41467-023-44372-y.
- Imai T, Lin J, Kaya GG, Ju E, Kondylis V, Kelepouras K, Liccardi G, Kim C, and Pasparakis M (2024). The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation. Immunity. doi:10.1016/j.immuni.2024.04.016.
- Injarabian L, Willenborg S, Welcker D, Sanin DE, Pasparakis M, Kashkar H, and Eming SA (2024). FADD- and RIPK3-Mediated Cell Death Ensures Clearance of Ly6C(high) Wound Macrophages from Damaged Tissue. J Invest Dermatol144, 152-164 e157. doi:10.1016/j.jid.2023.06.203.
- Koerner L, Wachsmuth L, Kumari S, Schwarzer R, Wagner T, Jiao H, and Pasparakis M (2024). ZBP1 causes inflammation by inducing RIPK3-mediated necroptosis and RIPK1 kinase activity-independent apoptosis. Cell Death Differ. doi:10.1038/s41418-024-01321-6.
- Moschandrea C, Kondylis V, Evangelakos I, Herholz M, Schneider F, Schmidt C, Yang M, Ehret S, Heine M, Jaeckstein MY, Szczepanowska K, Schwarzer R, Baumann L, Bock T, Nikitopoulou E, Brodesser S, Kruger M, Frezza C, Heeren J, Trifunovic A, and Pasparakis M (2024). Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes. Nature625, 385-392. doi:10.1038/s41586-023-06857-0.
2023
- Imanishi T, Unno M, Yoneda N, Motomura Y, Mochizuki M, Sasaki T, Pasparakis M, and Saito T (2023). RIPK1 blocks T cell senescence mediated by RIPK3 and caspase-8. Sci Adv 9, eadd6097. doi:10.1126/sciadv.add6097.
- Injarabian L, Willenborg S, Welcker D, Sanin DE, Pasparakis M, Kashkar H, and Eming SA (2024). FADD- and RIPK3-Mediated Cell Death Ensures Clearance of Ly6C(high) Wound Macrophages from Damaged Tissue. J Invest Dermatol 144, 152-164 e157. doi:10.1016/j.jid.2023.06.203.
- Koerner L, Schmiel M, Yang TP, Peifer M, Buettner R, and Pasparakis M (2023). NEMO- and RelA-dependent NF-kappaB signaling promotes small cell lung cancer. Cell Death Differ 30, 938-951. doi:10.1038/s41418-023-01112-5.
- Schorn F, Werthenbach JP, Hoffmann M, Daoud M, Stachelscheid J, Schiffmann LM, Hildebrandt X, Lyu SI, Peltzer N, Quaas A, Vucic D, Silke J, Pasparakis M, and Kashkar H (2023). cIAPs control RIPK1 kinase activity-dependent and -independent cell death and tissue inflammation. EMBO J 42, e113614. doi:10.15252/embj.2023113614.