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. INTRODUCTIONHermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by hypopigmentation, prolonged bleeding, and sometimes ceroid accumulation, lung fibrosis, and/or immune defects leading to premature death Wei, 2006). HPS or a similar disorder in mice results from mutations in any of at least 15 genes (Wei, 2006). All of these genes are ubiquitously expressed, but their mutation in HPS affects mainly the generation and function of selected tissuespecific lysosome-related organelles (LROs;Bonifacino, 2004;Di Pietro and Dell'Angelica, 2005). Those LROs that are most severely affected in all forms of HPS-pigment cell melanosomes, platelet dense granules, and lung lamellar bodies-are unique in that they coexist with bona fide lysosomes in their respective cell types (Dell'Angelica et al., 2000;Marks and Seabra, 2001). The 15 known HPS-associated genes have been identified, and although the products of most are thought to participate in trafficking events that are uniquely required to form this class of LRO, the function of only a few is understood in detail.The genes disrupted in human HPS-7 (Li et al., 2003) and HPS-8 (Morgan et al., 2006) and in the mouse HPS models pallid, muted, reduced pigmentation (rp), cappuccino, and sandy encode five of the eight known subunits of a stable protein complex known as biogenesis of lysosome-related organelles complex (BLOC)-1 (Falcon-Perez et al., 2002;Moriyama and Bonifacino, 2002;Ciciotte et al., 2003;Li et al., 2003;Gwynn et al., 2004;Starcevic and Dell'Angelica, 2004). To date, no specific subcellular function has been assigned...

The adaptor protein (AP)-3 complex is a component of the cellular machinery that controls protein sorting from endosomes to lysosomes and specialized related organelles such as melanosomes. Mutations in an AP-3 subunit underlie a form of Hermansky-Pudlak syndrome (HPS), a disorder characterized by abnormalities in lysosome-related organelles. HPS in humans can also be caused by mutations in genes encoding subunits of three complexes of unclear function, named biogenesis of lysosome-related organelles complex (BLOC)-1, -2, and -3. Here, we report that BLOC-1 interacts physically and functionally with AP-3 to facilitate the trafficking of a known AP-3 cargo, CD63, and of tyrosinase-related protein 1 (Tyrp1), a melanosomal membrane protein previously thought to traffic only independently of AP-3. BLOC-1 also interacts with BLOC-2 to facilitate Tyrp1 trafficking by a mechanism apparently independent of AP-3 function. Both BLOC-1 and -2 localize mainly to early endosome-associated tubules as determined by immunoelectron microscopy. These findings support the idea that BLOC-1 and -2 represent hitherto unknown components of the endosomal protein trafficking machinery.

Hermansky-Pudlak syndrome (HPS) defines a group of at least seven autosomal recessive disorders characterized by albinism and prolonged bleeding. These manifestations arise from defects in the biogenesis of lysosomerelated organelles, including melanosomes and platelet dense granules. Most genes associated with HPS in humans and rodent models of the disease encode components of multisubunit protein complexes that are expressed ubiquitously and play roles in intracellular protein trafficking and/or organelle distribution. A small GTPase of the Rab family, Rab38, is also implicated in the pathogenesis of the disease. This article reviews recent progress toward elucidating the cellular functions of these proteins.

Background: Lysosome-related organelles are a group of cell type-specific compartments with specialized functions, including melanosomes in melanocytes. Results: Cell type-specific Rab proteins, Rab32 and Rab38, colocalize and interact with the ubiquitous trafficking machinery in melanocytes. Conclusion: Rab32 and Rab38 cooperate with the ubiquitous trafficking machinery for melanosome biogenesis. Significance: Learning how lysosome-related organelles are built is key to understanding their biology.

During endocytosis, actin polymerization nucleated by the Arp2/3 complex provides force needed to drive internalization. Las17 is the strongest activator of the Arp2/3 complex in yeast cells. This study shows that Las17 is associated into a stable complex with Sla1, an adaptor that inhibits Las17 activity both in vitro and in vivo.