Biogenesis of lysosome-related organelles complex 3 (BLOC-3): A complex containing the Hermansky–Pudlak syndrome (HPS) proteins HPS1 and HPS4

doi:10.1073/pnas.1532040100

Biogenesis of lysosome-related organelles complex 3 (BLOC-3): A complex containing the Hermansky–Pudlak syndrome (HPS) proteins HPS1 and HPS4

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

Edited by Pietro V. De Camilli, Yale University School of Medicine, New Haven, CT, and approved June 5, 2003 (received for review April 7, 2003)

Abstract

Hermansky–Pudlak syndrome (HPS) defines a group of autosomal recessive disorders characterized by deficiencies in lysosome-related organelles such as melanosomes and platelet-dense granules. Several HPS genes encode proteins of unknown function including HPS1, HPS3, and HPS4. Here we have identified and characterized endogenous HPS3 and HPS4 proteins from HeLa cells. Both proteins were found in soluble and membrane-associated forms. Sedimentation-velocity and coimmunoprecipitation experiments revealed that HPS4 but not HPS3 associates with HPS1 in a complex, which we term biogenesis of lysosome-related organelles complex 3 (BLOC-3). Mutant fibroblasts deficient in either HPS1 or HPS4 displayed abnormal localization of lysosomes and late endosomes, which were less concentrated at the juxtanuclear region in mutant cells than in control fibroblasts. The coat-color phenotype of young homozygous double-mutant mice deficient in subunits of BLOC-3 (HPS1) and BLOC-1 (pallidin) was indistinguishable from that of BLOC-1 single mutants. Taken together, these observations suggest that HPS1 and HPS4 are components of a protein complex that regulates the intracellular localization of lysosomes and late endosomes and may function in a BLOC-1-dependent pathway for melanosome biogenesis.

Footnotes

↵ † To whom correspondence should be addressed at: Department of Human Genetics, University of California, Gonda 6357B, Los Angeles, CA 90095-7088. E-mail: edellangelica{at}mednet.ucla.edu.
↵ * R.N. and J.M.F.-P. contributed equally to this work.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: HPS, Hermansky–Pudlak syndrome; BLOC, biogenesis of lysosome-related organelles complex; LBPA, lysobisphosphatidic acid; Lamp, lysosome-associated membrane protein; EEA1, early endosome antigen 1.
Note Added in Proof. The association of HPS1 and HPS4 into a complex was reported independently by two recent papers (23, 24).