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Recruitment and assembly of endosomal sorting complex required for transport (ESCRT) I\u2013III rapidly counteracts membrane damage, but it is unclear\u00a0how ESCRT-I recognizes defective lysosomal membranes. Here, leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we identified LC3\/GABARAP-assisted stimulator for ESCRT recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes and couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is TFG, an endoplasmic reticulum exit-site-resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3 and GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit TSG101 via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT-I\u2013II\u2013III 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.<\/jats:p>","DOI":"10.1038\/s41586-026-10604-6","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T15:03:41Z","timestamp":1780499021000},"page":"216-226","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["LASER couples damage sensing to ESCRT assembly for lysosome repair"],"prefix":"10.1038","volume":"656","author":[{"given":"Claire S.","family":"Goul","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2159-0455","authenticated-orcid":false,"given":"Aakriti","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira","family":"Yitiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra E.","family":"Soltani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1787-2636","authenticated-orcid":false,"given":"Serim","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5141-0611","authenticated-orcid":false,"given":"Simon","family":"Rapp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2928-0159","authenticated-orcid":false,"given":"Martina","family":"Spacci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8712-3131","authenticated-orcid":false,"given":"Scot","family":"Federman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Sacco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huinan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8587-6532","authenticated-orcid":false,"given":"Lauren D.","family":"Enriquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nalan","family":"Liv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8598-4779","authenticated-orcid":false,"given":"Laralynne","family":"Przybyla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1611-1891","authenticated-orcid":false,"given":"Roberto","family":"Zoncu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"10604_CR1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.70044","volume":"240","author":"J Xun","year":"2025","unstructured":"Xun, J. & Tan, J. 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