biostudies-literatureHanna MGAligning Science Across Parkinson's (ASAP)NIDA NIH HHSHHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)HHS | NIH | National Institute on Drug Abuse (NIDA)Aligning Science Across Parkinson'sHHS | NIH | National Institute of Neurological Disorders and StrokeHHS | NIH | National Institute on Drug AbuseNCI NIH HHSNINDS NIH HHSHHS | NIH | NCI | Center for Cancer ResearchHHS | NIH | NCI | Center for Cancer Research (CCR)6168-6195https://www.ebi.ac.uk/biostudies/studies/S-EPMC12583604biostudies-literatureUnknown44(21)Recent studies have identified a family of rod-shaped proteins thought to mediate lipid transfer at intracellular membrane contacts by a bridge-like mechanism. We show that one such protein, bridge-like lipid transfer protein 3A (BLTP3A)/UHRF1BP1 binds VAMP7 vesicles via its C-terminal region, and anchors them to lysosomes via its chorein domain-containing N-terminal region binding to Rab7. Upon lysosome damage, BLTP3A-positive vesicles rapidly (within minutes) dissociate from lysosomes. Lysosome damage is known to activate the CASM (Conjugation of ATG8 to Single Membranes) pathway, leading to lipidation and lysosomal recruitment of mammalian ATG8 (mATG8) proteins. We find that this process drives the reassociation of BLTP3A with damaged lysosomes via an interaction of its LIR motif with mThe EMBO journalBLTP3A is associated with membranes of the late endocytic pathway and is an effector of CASM.PMC12583604ASAP-000580DA018343P30 CA008748NS36251R37 NS036251CA008748P30 DA018343R01 NS036251Fujise KHanna MGPang SLi ZRodriguez Cruz HOMonetti MDe Camilli PWu YXu CSfalseBLTP3A is associated with membranes of the late endocytic pathway and is an effector of CASM.Recent studies have identified a family of rod-shaped proteins thought to mediate lipid transfer at intracellular membrane contacts by a bridge-like mechanism. We show that one such protein, bridge-like lipid transfer protein 3A (BLTP3A)/UHRF1BP1 binds VAMP7 vesicles via its C-terminal region, and anchors them to lysosomes via its chorein domain-containing N-terminal region binding to Rab7. Upon lysosome damage, BLTP3A-positive vesicles rapidly (within minutes) dissociate from lysosomes. Lysosome damage is known to activate the CASM (Conjugation of ATG8 to Single Membranes) pathway, leading to lipidation and lysosomal recruitment of mammalian ATG8 (mATG8) proteins. We find that this process drives the reassociation of BLTP3A with damaged lysosomes via an interaction of its LIR motif with m2025-01-01T00:00:00Z2025 Nov2026-07-15T11:14:28.913Z2026-07-04T03:12:26.964ZS-EPMC125836044093589110.1038/s44318-025-00543-9