title: BLOC-1 and BLOC-3 regulate VAMP7 cycling to and from melanosomes via distinct tubular transport carriers.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Megan K
authors.identifier: 0000-0002-8986-5021
authors.initials: MK
authors.lastname: Dennis
authors.affiliation: Institut Curie, PSL Research University, Centre National de la Recherche Scientifique, UMR144, 75005 Paris, France Structure and Membrane Compartments, Institut Curie, 75005 Paris, France Cell and Tissue Imaging Facility (PICT-IBiSA), 75005 Paris, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Delevoye
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Amanda
authors.identifier: 0000-0002-7591-4128
authors.initials: A
authors.lastname: Acosta-Ruiz
authors.affiliation: Institut Curie, PSL Research University, Centre National de la Recherche Scientifique, UMR144, 75005 Paris, France Structure and Membrane Compartments, Institut Curie, 75005 Paris, France Cell and Tissue Imaging Facility (PICT-IBiSA), 75005 Paris, France.
authors.forename: Ilse
authors.identifier: 0000-0002-0097-7773
authors.initials: I
authors.lastname: Hurbain
authors.affiliation: Institut Curie, PSL Research University, Centre National de la Recherche Scientifique, UMR144, 75005 Paris, France Structure and Membrane Compartments, Institut Curie, 75005 Paris, France Cell and Tissue Imaging Facility (PICT-IBiSA), 75005 Paris, France.
authors.forename: Maryse
authors.initials: M
authors.lastname: Romao
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, England, UK.
authors.forename: Geoffrey G
authors.identifier: 0000-0002-5570-7615
authors.initials: GG
authors.lastname: Hesketh
authors.affiliation: Cell Biology and Genetics Research Centre, St. George's, University of London, London SW17 0RE, England, UK.
authors.forename: Philip S
authors.identifier: 0000-0003-4371-5527
authors.initials: PS
authors.lastname: Goff
authors.affiliation: Cell Biology and Genetics Research Centre, St. George's, University of London, London SW17 0RE, England, UK.
authors.forename: Elena V
authors.identifier: 0000-0002-4177-8236
authors.initials: EV
authors.lastname: Sviderskaya
authors.affiliation: Cell Biology and Genetics Research Centre, St. George's, University of London, London SW17 0RE, England, UK.
authors.forename: Dorothy C
authors.identifier: 0000-0002-3639-7527
authors.initials: DC
authors.lastname: Bennett
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, England, UK.
authors.forename: J Paul
authors.identifier: 0000-0003-3912-9760
authors.initials: JP
authors.lastname: Luzio
authors.affiliation: University Paris Diderot, Sorbonne Paris Cité, Institut Jacques Monod, CNRS UMR 7592, Membrane Traffic in Health and Disease, INSERM ERL U950, 75013 Paris, France.
authors.forename: Thierry
authors.identifier: 0000-0001-8514-7455
authors.initials: T
authors.lastname: Galli
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, England, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Owen
authors.affiliation: Institut Curie, PSL Research University, Centre National de la Recherche Scientifique, UMR144, 75005 Paris, France Structure and Membrane Compartments, Institut Curie, 75005 Paris, France Cell and Tissue Imaging Facility (PICT-IBiSA), 75005 Paris, France.
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 marksm@mail.med.upenn.edu.
authors.forename: Michael S
authors.identifier: 0000-0001-7435-7262
authors.initials: MS
authors.lastname: Marks
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D004705:Endocytosis; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins / Q000378:metabolism*; D008544:Melanocytes / Q000378:metabolism / Q000648:ultrastructure; D020460:Melanosomes / Q000378:metabolism* / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D010858:Pigmentation; D021381:Protein Transport; D050765:Qa-SNARE Proteins / Q000378:metabolism; D050683:R-SNARE Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: C000619640:BLOC1S1 protein, mouse; C513476:Bloc1s6 protein, mouse; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D011993:Recombinant Fusion Proteins; C496927:Sybl1 protein, mouse; D049452:Green Fluorescent Proteins; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse; D020691:rab GTP-Binding Proteins