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Vol. 17, Issue 9, 4014-4026, September 2006
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*Department of Cell Biology, Graduate Program in Biochemistry, Cell, and Developmental Biology, **Center for Neurodegenerative Disease, and ¶Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; ||College of Health and Human Sciences, Georgia State University, Atlanta, GA 30302; #Department of Human Genetics, University of California, Los Angeles, CA 90095; and @Cambridge Institute for Medical Research, Cambridge CB2 2XY, United Kingdom
Submitted February 6, 2006;
Revised May 16, 2006;
Accepted May 31, 2006
Monitoring Editor: Sandra Lemmon
Mutational analyses have revealed many genes that are required for proper biogenesis of lysosomes and lysosome-related organelles. The proteins encoded by these genes assemble into five distinct complexes (AP-3, BLOC-1-3, and HOPS) that either sort membrane proteins or interact with SNAREs. Several of these seemingly distinct complexes cause similar phenotypic defects when they are rendered defective by mutation, but the underlying cellular mechanism is not understood. Here, we show that the BLOC-1 complex resides on microvesicles that also contain AP-3 subunits and membrane proteins that are known AP-3 cargoes. Mouse mutants that cause BLOC-1 or AP-3 deficiencies affected the targeting of LAMP1, phosphatidylinositol-4-kinase type II alpha, and VAMP7-TI. VAMP7-TI is an R-SNARE involved in vesicle fusion with late endosomes/lysosomes, and its cellular levels were selectively decreased in cells that were either AP-3- or BLOC-1–deficient. Furthermore, BLOC-1 deficiency selectively altered the subcellular distribution of VAMP7-TI cognate SNAREs. These results indicate that the BLOC-1 and AP-3 protein complexes affect the targeting of SNARE and non-SNARE AP-3 cargoes and suggest a function of the BLOC-1 complex in membrane protein sorting.
These authors contributed equally to this work.
These authors contributed equally to this work.
Address correspondence to: Victor Faundez ( faundez{at}cellbio.emory.edu)
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