BLOC-1 and BLOC-3 regulate VAMP7 cycling to and from melanosomes via distinct tubular transport carriers

J Cell Biol. 2016 Aug 1;214(3):293-308. doi: 10.1083/jcb.201605090.


Endomembrane organelle maturation requires cargo delivery via fusion with membrane transport intermediates and recycling of fusion factors to their sites of origin. Melanosomes and other lysosome-related organelles obtain cargoes from early endosomes, but the fusion machinery involved and its recycling pathway are unknown. Here, we show that the v-SNARE VAMP7 mediates fusion of melanosomes with tubular transport carriers that also carry the cargo protein TYRP1 and that require BLOC-1 for their formation. Using live-cell imaging, we identify a pathway for VAMP7 recycling from melanosomes that employs distinct tubular carriers. The recycling carriers also harbor the VAMP7-binding scaffold protein VARP and the tissue-restricted Rab GTPase RAB38. Recycling carrier formation is dependent on the RAB38 exchange factor BLOC-3. Our data suggest that VAMP7 mediates fusion of BLOC-1-dependent transport carriers with melanosomes, illuminate SNARE recycling from melanosomes as a critical BLOC-3-dependent step, and likely explain the distinct hypopigmentation phenotypes associated with BLOC-1 and BLOC-3 deficiency in Hermansky-Pudlak syndrome variants.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Cell Membrane / metabolism
  • Cell Membrane / ultrastructure
  • Endocytosis*
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lectins / metabolism*
  • Melanocytes / metabolism
  • Melanocytes / ultrastructure
  • Melanosomes / metabolism*
  • Melanosomes / ultrastructure
  • Membrane Glycoproteins / metabolism
  • Mice, Inbred C57BL
  • Mitochondrial Proteins
  • Nerve Tissue Proteins / metabolism*
  • Oxidoreductases / metabolism
  • Pigmentation
  • Protein Transport
  • Qa-SNARE Proteins / metabolism
  • R-SNARE Proteins / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Transport Vesicles / metabolism*
  • Transport Vesicles / ultrastructure
  • rab GTP-Binding Proteins / metabolism


  • BLOC1S1 protein, mouse
  • Bloc1s6 protein, mouse
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lectins
  • Membrane Glycoproteins
  • Mitochondrial Proteins
  • Nerve Tissue Proteins
  • Qa-SNARE Proteins
  • R-SNARE Proteins
  • Recombinant Fusion Proteins
  • Sybl1 protein, mouse
  • Green Fluorescent Proteins
  • Oxidoreductases
  • Tyrp1 protein, mouse
  • rab GTP-Binding Proteins