title: BLOC-1 is required for cargo-specific sorting from vacuolar early endosomes toward lysosome-related organelles.
abstract: Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defects in the formation and function of lysosome-related organelles such as melanosomes. HPS in humans or mice is caused by mutations in any of 15 genes, five of which encode subunits of biogenesis of lysosome-related organelles complex (BLOC)-1, a protein complex with no known function. Here, we show that BLOC-1 functions in selective cargo exit from early endosomes toward melanosomes. BLOC-1-deficient melanocytes accumulate the melanosomal protein tyrosinase-related protein-1 (Tyrp1), but not other melanosomal proteins, in endosomal vacuoles and the cell surface due to failed biosynthetic transit from early endosomes to melanosomes and consequent increased endocytic flux. The defects are corrected by restoration of the missing BLOC-1 subunit. Melanocytes from HPS model mice lacking a different protein complex, BLOC-2, accumulate Tyrp1 in distinct downstream endosomal intermediates, suggesting that BLOC-1 and BLOC-2 act sequentially in the same pathway. By contrast, intracellular Tyrp1 is correctly targeted to melanosomes in melanocytes lacking another HPS-associated protein complex, adaptor protein (AP)-3. The results indicate that melanosome maturation requires at least two cargo transport pathways directly from early endosomes to melanosomes, one pathway mediated by AP-3 and one pathway mediated by BLOC-1 and BLOC-2, that are deficient in several forms of HPS.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Subba Rao Gangi
authors.initials: SR
authors.lastname: Setty
authors.forename: Danièle
authors.initials: D
authors.lastname: Tenza
authors.forename: Steven T
authors.initials: ST
authors.lastname: Truschel
authors.forename: Evelyn
authors.initials: E
authors.lastname: Chou
authors.forename: Elena V
authors.initials: EV
authors.lastname: Sviderskaya
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Theos
authors.forename: M Lynn
authors.initials: ML
authors.lastname: Lamoreux
authors.forename: Santiago M
authors.initials: SM
authors.lastname: Di Pietro
authors.forename: Marta
authors.initials: M
authors.lastname: Starcevic
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
authors.forename: Esteban C
authors.initials: EC
authors.lastname: Dell'Angelica
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marks
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008543:Melanins / Q000096:biosynthesis; D020460:Melanosomes / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D010088:Oxidoreductases / Q000737:chemistry; D010858:Pigmentation / Q000502:physiology; D021381:Protein Transport; D050765:Qa-SNARE Proteins / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D033963:Adaptor Protein Complex 3; D008543:Melanins; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D050765:Qa-SNARE Proteins; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse; D014442:Monophenol Monooxygenase