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The bridge-like lipid transport protein VPS13C/PARK23 mediates ER-lysosome contacts upon lysosome damage
Published April 15, 2025
Output Details
Published April 15, 2025
Description
Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in
Parkinson's disease (PD). Here we show that VPS13C, a bridge-like lipid transport protein and a
PD gene, is a sensor of lysosome stress or damage. Upon lysosome membrane perturbation,
VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their
membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged
lysosome surface that releases an inhibited state of VPS13C which hinders access of its VAB
domain to lysosome-bound Rab7. While another PD protein, LRRK2, is also recruited to stressed
or damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms.
Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery
to lysosomes by VPS13C is part of an early protective response to lysosome damage.
Identifier (DOI)
10.1038/s41556-025-01653-6