BLTP3A is associated with membranes of the late endocytic pathway and is an effector of CASM

EMBO J. 2025 Nov;44(21):6168-6195. doi: 10.1038/s44318-025-00543-9. Epub 2025 Sep 11.

Abstract

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 mATG8 which coincides with a dissociation from the vesicles. Our findings reveal that BLTP3A is an effector of CASM, potentially as part of a mechanism to help repair or minimize lysosome damage.

Keywords: BLTP3; LC3; Lysosome; Rab45; Urate Crystals.

MeSH terms

  • Animals
  • Autophagy-Related Protein 8 Family / genetics
  • Autophagy-Related Protein 8 Family / metabolism
  • Carrier Proteins* / genetics
  • Carrier Proteins* / metabolism
  • Endocytosis*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lysosomes* / metabolism
  • Protein Binding
  • R-SNARE Proteins / genetics
  • R-SNARE Proteins / metabolism
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism
  • rab7 GTP-Binding Proteins

Substances

  • R-SNARE Proteins
  • rab7 GTP-Binding Proteins
  • Autophagy-Related Protein 8 Family
  • rab GTP-Binding Proteins
  • rab7 GTP-binding proteins, human
  • VAMP7 protein, human
  • Carrier Proteins