Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 23, Issue 16, Pages 3178-3192Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E11-06-0509
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Funding
- National Institutes of Health Grant from the National Eye Institute [R01 EY015625]
- Institut Curie and Centre National de la Recherche Scientifique
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Wellcome Trust [078327]
- [T32 GM007229]
- [T32 HL007971]
- [K12 GM081259]
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Cell types that generate unique lysosome-related organelles (LROs), such as melanosomes in melanocytes, populate nascent LROs with cargoes that are diverted from endosomes. Cargo sorting toward melanosomes correlates with binding via cytoplasmically exposed sorting signals to either heterotetrameric adaptor AP-1 or AP-3. Some cargoes bind both adaptors, but the relative contribution of each adaptor to cargo recognition and their functional interactions with other effectors during transport to melanosomes are not clear. Here we exploit targeted mutagenesis of the acidic dileucine-based sorting signal in the pigment cell-specific protein OCA2 to dissect the relative roles of AP-1 and AP-3 in transport to melanosomes. We show that binding to AP-1 or AP-3 depends on the primary sequence of the signal and not its position within the cytoplasmic domain. Mutants that preferentially bound either AP-1 or AP-3 each trafficked toward melanosomes and functionally complemented OCA2 deficiency, but AP-3 binding was necessary for steady-state melanosome localization. Unlike tyrosinase, which also engages AP-3 for optimal melanosomal delivery, both AP-1- and AP-3-favoring OCA2 variants required BLOC-1 for melanosomal transport. These data provide evidence for distinct roles of AP-1 and AP-3 in OCA2 transport to melanosomes and indicate that BLOC-1 can cooperate with either adaptor during cargo sorting to LROs.
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