ATXN3 regulates lysosome regeneration after damage by targeting K48-K63-branched ubiquitin chains

TY - JOUR

T1 - ATXN3 regulates lysosome regeneration after damage by targeting K48-K63-branched ubiquitin chains

AU - Reinders, Maike

AU - Kravic, Bojana

AU - Gahlot, Pinki

AU - Koska, Sandra

AU - van den Boom, Johannes

AU - Schulze, Nina

AU - Levantovsky, Sophie

AU - Kleine, Stefan

AU - Kaiser, Markus

AU - Kulathu, Yogesh

AU - Behrends, Christian

AU - Meyer, Hemmo

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/9/15

Y1 - 2025/9/15

N2 - 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.

AB - 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.

KW - Autophagy

KW - Lysosome

KW - Membrane

KW - Stress Response

KW - Ubiquitin

UR - https://www.scopus.com/pages/publications/105012228302

U2 - 10.1038/s44318-025-00517-x

DO - 10.1038/s44318-025-00517-x

M3 - Article

C2 - 40730717

AN - SCOPUS:105012228302

SN - 0261-4189

VL - 44

SP - 5086

EP - 5111

JO - EMBO Journal

JF - EMBO Journal

IS - 18

ER -