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Vol. 17, Issue 9, 4027-4038, September 2006
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*Department of Human Genetics, University of California, Los Angeles, CA 90095; Institut Curie, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 144, Paris 75248, France; and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
Submitted May 3, 2006;
Revised June 26, 2006;
Accepted July 5, 2006
Monitoring Editor: Sandra Schmid
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.
The online version of this contains supplemental material at MBC Online (http://www.molbiolcell.org). This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-05-0379) on July 12, 2006.
Address correspondence to: Esteban C. Dell’Angelica (Edellangelica{at}mednet.ucla.edu)
Abbreviations used: AP, adaptor protein; BLOC, biogenesis of lysosome-related organelles complex; EEA1, early endosome antigen 1; HPS, Hermansky-Pudlak syndrome; HRP, horseradish peroxidase; LAMP, lysosome-associated membrane protein; mAb, monoclonal antibody; siRNA, small interference RNA; Tf, transferrin; TfR, transferrin receptor; Tyrp1, tyrosinase-related protein 1.
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