title: BLOC-2 targets recycling endosomal tubules to melanosomes for cargo delivery.
abstract: Hermansky-Pudlak syndrome (HPS) is a group of disorders characterized by the malformation of lysosome-related organelles, such as pigment cell melanosomes. Three of nine characterized HPS subtypes result from mutations in subunits of BLOC-2, a protein complex with no known molecular function. In this paper, we exploit melanocytes from mouse HPS models to place BLOC-2 within a cargo transport pathway from recycling endosomal domains to maturing melanosomes. In BLOC-2-deficient melanocytes, the melanosomal protein TYRP1 was largely depleted from pigment granules and underwent accelerated recycling from endosomes to the plasma membrane and to the Golgi. By live-cell imaging, recycling endosomal tubules of wild-type melanocytes made frequent and prolonged contacts with maturing melanosomes; in contrast, tubules from BLOC-2-deficient cells were shorter in length and made fewer, more transient contacts with melanosomes. These results support a model in which BLOC-2 functions to direct recycling endosomal tubular transport intermediates to maturing melanosomes and thereby promote cargo delivery and optimal pigmentation.
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Dennis
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Adriana R
authors.initials: AR
authors.lastname: Mantegazza
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Olivia L
authors.initials: OL
authors.lastname: Snir
authors.affiliation: Institut Curie, Centre de Recherche; Structure and Membrane Compartments, Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 144; and Cell and Tissue Imaging Facility, Centre National de la Recherche Scientifique UMR144, Paris F-75248, France Institut Curie, Centre de Recherche; Structure and Membrane Compartments, Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 144; and Cell and Tissue Imaging Facility, Centre National de la Recherche Scientifique UMR144, Paris F-75248, France.
authors.forename: Danièle
authors.initials: D
authors.lastname: Tenza
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Amanda
authors.initials: A
authors.lastname: Acosta-Ruiz
authors.affiliation: Institut Curie, Centre de Recherche; Structure and Membrane Compartments, Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 144; and Cell and Tissue Imaging Facility, Centre National de la Recherche Scientifique UMR144, Paris F-75248, France Institut Curie, Centre de Recherche; Structure and Membrane Compartments, Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 144; and Cell and Tissue Imaging Facility, Centre National de la Recherche Scientifique UMR144, Paris F-75248, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Delevoye
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Richard
authors.initials: R
authors.lastname: Zorger
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Anand
authors.initials: A
authors.lastname: Sitaram
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Wilfredo
authors.initials: W
authors.lastname: de Jesus-Rojas
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India 560 012.
authors.forename: Keerthana
authors.initials: K
authors.lastname: Ravichandran
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104 In Silico Molecular, LLC, Blue Bell, PA 19422.
authors.forename: John
authors.initials: J
authors.lastname: Rux
authors.affiliation: Molecular Cell Sciences Research Centre, St. George's, University of London, London SW17 0RE, England, UK.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Sviderskaya
authors.affiliation: Molecular Cell Sciences Research Centre, St. George's, University of London, London SW17 0RE, England, UK.
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
authors.affiliation: Institut Curie, Centre de Recherche; Structure and Membrane Compartments, Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 144; and Cell and Tissue Imaging Facility, Centre National de la Recherche Scientifique UMR144, Paris F-75248, France Institut Curie, Centre de Recherche; Structure and Membrane Compartments, Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 144; and Cell and Tissue Imaging Facility, Centre National de la Recherche Scientifique UMR144, Paris F-75248, France Institut Curie, Centre de Recherche; Structure and Membrane Compartments, Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 144; and Cell and Tissue Imaging Facility, Centre National de la Recherche Scientifique UMR144, Paris F-75248, France.
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104 Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104 marksm@mail.med.upenn.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marks
authors.affiliation: Department of Pathology and Laboratory Medicine, Department of Physiology, and Penn Vision Research Center, University of Pennsylvania, Philadelphia, PA 19104 Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India 560 012.
authors.forename: Subba Rao Gangi
authors.initials: SR
authors.lastname: Setty
mesh_terms: D000818:Animals; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008544:Melanocytes / Q000378:metabolism; D020460:Melanosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010088:Oxidoreductases / Q000378:metabolism; D021381:Protein Transport; D012880:Skin Pigmentation; D033921:Vesicular Transport Proteins / Q000502:physiology*
chemical_list: C554282:Hps6 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D033921:Vesicular Transport Proteins; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse