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TitleCathepsin-dependent amyloid formation drives mechanical rupture of lysosomal membranes.
Journal, issue, pagesbioRxiv, Year 2026
Publish dateJan 19, 2026
AuthorsDelong Li / Wenxin Zhang / Michaela Medina / Jan F M Stuke / Andre Schwarz / Jonas Brill / Johann Brenner / Felix Kraus / Simon Ohlerich / Javier Lizarrondo / Jeremy Pflaum / Julia H Grass / Lena-Marie Soltow / Dietmar Hammerschmid / Natalie Weber / Sonja Welsch / Julian D Langer / Maike Windbergs / J Wade Harper / Erin Schuman / Gerhard Hummer / Danielle A Grotjahn / Florian Wilfling
PubMed AbstractLysosomal membrane integrity is essential for cellular homeostasis, and its failure drives lysosomal storage disorders (LSD) and neurodegeneration. The dipeptide L-leucyl-L-leucine methyl ester ...Lysosomal membrane integrity is essential for cellular homeostasis, and its failure drives lysosomal storage disorders (LSD) and neurodegeneration. The dipeptide L-leucyl-L-leucine methyl ester (LLOMe) is widely used to model lysosomal damage, yet its mechanism remains poorly understood. The prevailing view holds that LLOMe polymerizes into membrane-permeabilizing peptide chains within the lysosomal lumen. Using cryo-electron tomography in cultured cells and primary neurons, we visualized the structural basis of LLOMe-induced lysosomal damage. We reveal that LLOMe forms amyloid structures within lysosomes that directly interact with and rupture the limiting membrane through mechanical stress. reconstitution confirms this amyloid-mediated mechanism. These findings establish a structural paradigm for lysosomal membrane disruption and provide insights into how disease-relevant protein aggregates, implicated in neurodegeneration and LSD, may compromise lysosomal integrity.
External linksbioRxiv / PubMed:41648416 / PubMed Central
MethodsEM (subtomogram averaging) / EM (tomography)
Resolution18.74 Å
Structure data

EMDB-56238: In situ cryo-ET subtomogram averaged map of Flotillin complex
Method: EM (subtomogram averaging) / Resolution: 18.74 Å

EMDB-56295: In situ cryo-ET tomogram of a lysosomal structure in untreated HeLa TMEM192-3xHA cell.
Method: EM (tomography)

EMDB-56296: In situ cryo-ET tomogram of lysosome damaged by LLOMe (0.5mM, 60min) in HeLa TMEM192-3xHA cell.
Method: EM (tomography)

EMDB-56297: In situ cryo-ET of lysosome damaged by LLOMe (0.5mM, 60min) encapsulated in an autophagosome in HeLa TMEM192-3xHA cell.
Method: EM (tomography)

EMDB-56298: In situ cryo-ET tomogram of lysosomes in BAPTA AM pre-treated (50uM, 30min) and LLOMe (0.5mM, 60min) treated TMEM192-3xHA HeLa cell.
Method: EM (tomography)

EMDB-56300: In situ cryo-ET tomogram of lysosomes in LLOMe (0.5mM, 60min) treated TMEM192-3xHA HeLa cell.
Method: EM (tomography)

EMDB-56327: In situ cryo-ET tomogram of lysosomal structure in untreated rat hippocampal neurons
Method: EM (tomography)

EMDB-56329: In situ cryo-ET tomogram of lysosomes in E64d pre-treated (20uM, 30min) and LLOMe (0.5mM, 60min) treated TMEM192-3xHA HeLa cell.
Method: EM (tomography)

EMDB-56330: In situ cryo-ET tomogram of lysosomal structure in LLOMe-treated (0.5mM, 1h) rat hippocampal neuron.
Method: EM (tomography)

Source
  • Homo sapiens (human)
  • Rattus (rats)

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