Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH

Presenting author: Pinki Gahlot

Universität Duisburg-Essen, Fakultät für Biologie, Universitätstraße 5, 45141 Essen [DE], pinki.gahlot@uni-due.de

Author(s):
Pinki Gahlot, Bojana Kravic, Giulia Rota, Johannes van den Boom, Sophie Levantovsky, Nina Schulze, Christian Behrends, Hemmo Meyer

Lysosomes are the main degradative organelles in the cell and serve as platforms for important signalling pathways. The loss of lysosomal function due to lysosomal membrane permeabilization (LMP) can be highly deleterious for the cell. LMP can be caused by different conditions such as lipid peroxidation, lysosomotropic drugs or disease-associated changes in lipid composition. Cells respond to LMP by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy. However, it is not fully understood how the decision between repair and lysophagy of damaged lysosomes 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. These lipid-packing defects are sensed via amphipathic helices in SPG20. 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.

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