ORCID: https://orcid.org/0000-0002-4425-3494; Kravic, Bojana; Gahlot, Pinki ORCID: https://orcid.org/0009-0000-8175-045X; Koska, Sandra; Boom, Johannes van den ORCID: https://orcid.org/0000-0002-2075-9351; Schulze, Nina ORCID: https://orcid.org/0009-0008-5503-6218; Levantovsky, Sophie ORCID: https://orcid.org/0000-0002-0918-6871; Klein, Stefan ORCID: https://orcid.org/0000-0002-8228-0231; Kaiser, Markus ORCID: https://orcid.org/0000-0002-6540-8520; Kulathu, Yogesh ORCID: https://orcid.org/0000-0002-3274-1642; Behrends, Christian ORCID: https://orcid.org/0000-0002-9184-7607 und Meyer, Hemmo ORCID: https://orcid.org/0000-0003-1883-1796
(2025):
ATXN3 regulates lysosome regeneration after damage by targeting K48-K63-branched ubiquitin chains.
In: EMBO Journal, Bd. 44: S. 5086-5111
[PDF, 4MB]
Abstract
The cellular response to lysosomal damage involves fine-tuned mechanisms of membrane repair, lysosome regeneration and lysophagy, but how these different processes are coordinated is unclear. Here we show in human cells that the deubiquitinating enzyme ATXN3 helps restore integrity of the lysosomal system after damage by targeting K48-K63-branched ubiquitin chains on regenerating lysosomes. We find that ATXN3 is required for lysophagic flux after lysosomal damage but is not involved in the initial phagophore formation on terminally damaged lysosomes. Instead, ATXN3 is recruited to a distinct subset of lysosomes that are decorated with phosphatidylinositol-(4,5)-bisphosphate and that are not yet fully reacidified. There, ATXN3, along with its partner VCP/p97, targets and turns over K48-K63-branched ubiquitin conjugates. ATXN3 thus facilitates degradation of a fraction of LAMP2 via microautophagy to regenerate the lysosomal membrane and to thereby reestablish degradative capacity needed also for completion of lysophagy. Our findings identify a key role of ATXN3 in restoring lysosomal function after lysosomal membrane damage and uncover K48-K63-branched ubiquitin chain-regulated regeneration as a critical element of the lysosomal damage stress response.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Medizin > Munich Cluster for Systems Neurology (SyNergy) |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| URN: | urn:nbn:de:bvb:19-epub-129926-5 |
| ISSN: | 0261-4189 |
| Sprache: | Englisch |
| Dokumenten ID: | 129926 |
| Datum der Veröffentlichung auf Open Access LMU: | 01. Dez. 2025 07:26 |
| Letzte Änderungen: | 01. Dez. 2025 07:26 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 447112704 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 424228829 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 259130777 |
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