000K utf8 1100 2024$c2024-03-18 1500 eng 2050 urn:nbn:de:hbz:465-20250102-095635-6 2051 10.1016/j.molcel.2024.02.029 3000 Gahlot, Pinki 3010 Behrends, Christian 3010 Kravic, Bojana 3010 Levantovsky, Sophie 3010 Maspero, Elena 3010 Meyer, Hemmo 3010 Polo, Simona 3010 Rota, Giulia 3010 Schulze, Nina 3010 van den Boom, Johannes 4000 Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH [Gahlot, Pinki] 4209 Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully understood how this decision is made. Here, we uncover a pathway in human cells that detects lipid bilayer perturbations in the limiting membrane of compromised lysosomes, which fail to be repaired, and then initiates ubiquitin-triggered lysophagy. We find that SPG20 binds the repair factor IST1 on damaged lysosomes and, importantly, integrates that with the detection of damage-associated lipid-packing defects of the lysosomal membrane. Detection occurs via sensory amphipathic helices in SPG20 before rupture of the membrane. If lipid-packing defects are extensive, such as during lipid peroxidation, SPG20 recruits and activates ITCH, which marks the damaged lysosome with lysine-63-linked ubiquitin chains to initiate lysophagy and thus triages the lysosome for destruction. With SPG20 being linked to neurodegeneration, these findings highlight the relevance of a coordinated lysosomal damage response for cellular homeostasis. 4950 https://doi.org/10.1016/j.molcel.2024.02.029$xR$3Volltext$534 4950 https://nbn-resolving.org/urn:nbn:de:hbz:465-20250102-095635-6$xR$3Volltext$534 4961 https://duepublico2.uni-due.de/receive/duepublico_mods_00082018 5051 570 5550 ESCRT 5550 e spartin 5550 ITCH 5550 lipid sensing 5550 lysophagy 5550 lysosomal membrane permeabilization 5550 lysosomal repair 5550 spastic paraplegia 5550 Troyer syndrom 5550 ubiquitin