{
  "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 it is unclear how 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-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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA",
    "Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA. aakriti.jain@utsouthwestern.edu",
    "Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. aakriti.jain@utsouthwestern.edu",
    "Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA",
    "Laboratory for Genomics Research, San Francisco, CA, USA",
    "Center for Molecular Medicine, University Medical Center Utrecht, Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands",
    "Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA. rzoncu@berkeley.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Claire S. Goul",
      "orcid": "0000-0002-6556-9631"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Aakriti Jain",
      "orcid": "0000-0002-2159-0455"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Samira Yitiz"
    },
    {
      "affs": [
        5
      ],
      "name": "Zahra E. Soltani",
      "orcid": "0009-0008-6674-9635"
    },
    {
      "affs": [
        0
      ],
      "name": "Serim Yang",
      "orcid": "0009-0001-1787-2636"
    },
    {
      "affs": [
        0
      ],
      "name": "Simon Rapp",
      "orcid": "0000-0002-5141-0611"
    },
    {
      "affs": [
        0
      ],
      "name": "Martina Spacci",
      "orcid": "0009-0006-2928-0159"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Scot Federman",
      "orcid": "0000-0001-8712-3131"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "James Sacco"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Huinan Li"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Lauren D. Enriquez",
      "orcid": "0000-0002-8587-6532"
    },
    {
      "affs": [
        5
      ],
      "name": "Nalan Liv",
      "orcid": "0000-0003-2654-9117"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Laralynne Przybyla",
      "orcid": "0000-0002-8598-4779"
    },
    {
      "affs": [
        6
      ],
      "name": "Roberto Zoncu",
      "orcid": "0000-0003-1611-1891"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2whth13pm0w5q.bib",
  "cited_by": 10,
  "doi": "10.1038/s41586-026-10604-6",
  "fulltext_url": null,
  "id": "2whth13pm0w5q",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10604-6",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1307|Cellular transport and secretion"
    ]
  ],
  "openalex": "W7163409597",
  "pdf_url": null,
  "pmcid": "PMC13442042",
  "pmid": "42236937",
  "published": "2026-06-03",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/2whth13pm0w5q.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:46Z",
      "native_id": "W7163409597",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-10604-6"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1307|Cellular transport and secretion",
      "subfield": "cell-biology"
    }
  ],
  "title": "LASER couples damage sensing to ESCRT assembly for lysosome repair",
  "title_text": "LASER couples damage sensing to ESCRT assembly for lysosome repair",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T13:20:49Z",
  "url": "https://research.draconitic.com/paper/2whth13pm0w5q",
  "venue": "Nature",
  "versions": []
}