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Peer-reviewedCC BYNature

LASER couples damage sensing to ESCRT assembly for lysosome repair

  • Claire S. Goul1
  • Aakriti Jain2,3
  • Samira Yitiz4,5
  • Zahra E. Soltani6
  • Serim Yang1
  • Simon Rapp1
  • Martina Spacci1
  • Scot Federman4,5
  • James Sacco4,5
  • Huinan Li4,5
  • Lauren D. Enriquez4,5
  • Nalan Liv6
2 more authors
  • Laralynne Przybyla4,5
  • Roberto Zoncu7
7 affiliations
  1. 1Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA
  2. 2Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA. [email protected]
  3. 3Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected]
  4. 4Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
  5. 5Laboratory for Genomics Research, San Francisco, CA, USA
  6. 6Center for Molecular Medicine, University Medical Center Utrecht, Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands
  7. 7Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA. [email protected]
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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.

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Cite

BibTeXRIS
BibTeX
@article{goul2026laser,
  title = {{LASER couples damage sensing to ESCRT assembly for lysosome repair}},
  author = {Claire S. Goul and Aakriti Jain and Samira Yitiz and Zahra E. Soltani and Serim Yang and Simon Rapp and Martina Spacci and Scot Federman and James Sacco and Huinan Li and Lauren D. Enriquez and Nalan Liv and Laralynne Przybyla and Roberto Zoncu},
  journal = {Nature},
  year = {2026},
  month = jun,
  doi = {10.1038/s41586-026-10604-6},
  url = {https://doi.org/10.1038/s41586-026-10604-6},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - LASER couples damage sensing to ESCRT assembly for lysosome repair
AU  - Claire S. Goul
AU  - Aakriti Jain
AU  - Samira Yitiz
AU  - Zahra E. Soltani
AU  - Serim Yang
AU  - Simon Rapp
AU  - Martina Spacci
AU  - Scot Federman
AU  - James Sacco
AU  - Huinan Li
AU  - Lauren D. Enriquez
AU  - Nalan Liv
AU  - Laralynne Przybyla
AU  - Roberto Zoncu
PY  - 2026
DA  - 2026/06/03
JO  - Nature
DO  - 10.1038/s41586-026-10604-6
UR  - https://doi.org/10.1038/s41586-026-10604-6
AB  - 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.
SN  - 0028-0836
SN  - 1476-4687
ER  -