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A ubiquitin ligase protects lysosomes from CLN4 mutant-induced membrane damages

ABSTRACT: Understanding how cells mitigate lysosomal damage is critical for unraveling pathogenic mechanisms of lysosome related diseases. Here we use organelle-specific proteomics in iPSC derived neurons (i3Neuron) and an in vitro lysosome damaging assay to demonstrate that lysosome damage, caused by the aggregation of Ceroid Lipofuscinosis Neuronal 4 (CLN4) linked DNAJC5 mutants on lysosomal membranes, serves as a critical pathogenic linchpin in CLN4 associated neurodegeneration. Intriguingly, in non neuronal cells, a ubiquitin dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4 associated lysotoxicity. Genome wide CRISPR screens identify the ubiquitin ligase CHIP as a central microautophagy regulator that confers ubiquitin dependent lysosome protection. Importantly, CHIP lysosome protection function is transferrable, as ectopic CHIP improves lysosomal function in CLN4 i3Neurons, and effectively alleviates lipofuscin accumulation and neurodegeneration in a Drosophila CLN4 disease model. Our study establishes CHIP mediated microautophagy as a key organelle damage guardian that preserves lysosome integrity, offering new insights into therapeutic development for CLN4 and other lysosome related neurodegenerative diseases.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: ling hao

PROVIDER: MSV000096646 | MassIVE | Wed Dec 11 12:53:00 GMT 2024

SECONDARY ACCESSION(S): PXD058788

REPOSITORIES: MassIVE

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