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LASER couples damage sensing to ESCRT assembly for lysosome repair

ABSTRACT: Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of Endosomal Sorting Complex Required for Transport (ESCRT) I-III rapidly counteracts membrane damage, but how ESCRT-I recognizes defective lysosomal membranes is unclear. Leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we discovered LC3/GABARAP Assisted Stimulator for ESCRT Recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes, and which couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is Trk-fused gene (TFG), an ER exit sites (ERES) resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3/GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit, Tumor Suppressor Gene 101 (TSG101), via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT I-II-III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328484 | GEO | 2026/04/20

REPOSITORIES: GEO

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