BLOC-1 is Required for Cargo-specific Sorting from Vacuolar Early Endosomes Toward Lysosome-related Organelles

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2006 Dec 22

PMID 17182842

Citations 129

Authors

Subba Rao Gangi Setty

Daniele Tenza

Steven T Truschel

Evelyn Chou

Elena V Sviderskaya

Alexander C Theos

M Lynn Lamoreux

Santiago M Di Pietro

Marta Starcevic

Dorothy C Bennett

Esteban C DellAngelica

Graca Raposo

Michael S Marks

Affiliations

Soon will be listed here.

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.

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