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A more recent version of this article appeared on March 1, 2007
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Submitted on December 4, 2006
Accepted on December 7, 2006
*Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104; Institut Curie, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 144, Paris 75248, France; Department of Basic Medical Sciences, St. George’s Hospital Medical School, London, SW17 ORE, United Kingdom; Comparative Genetics Program, Texas A&M University, College Station, TX 77843; ||Department of Human Genetics, University of California, Los Angeles, CA 90095
Monitoring Editor: Sandra Schmid
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 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 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, AP-3. The results indicate that melanosome maturation requires at least two cargo transport pathways directly from early endosomes to melanosomes, one mediated by AP-3 and another by BLOC-1 and BLOC-2, that are deficient in several forms of HPS.
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