BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related Organelles

TLDR

Hermansky‑Pudlak syndrome is a genetic disorder caused by mutations in 15 genes, including five that encode subunits of the BLOC‑1 complex, whose role in lysosome‑related organelle biogenesis is unknown. BLOC‑1 is essential for selective exit of the melanosomal protein Tyrp1 from early endosomes to melanosomes; loss of BLOC‑1 causes Tyrp1 accumulation in endosomal vacuoles and on the cell surface, which is rescued by subunit restoration, and the data reveal that melanosome maturation relies on two distinct early‑endosome‑to‑melanosome transport routes—one mediated by AP‑3 and another by BLOC‑1/BLOC‑2.

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.