Abstract
The dense-core vesicle is a secretory organelle that mediates the regulated release of peptide hormones, growth factors, and biogenic amines. Dense-core vesicles originate from the trans-Golgi of neurons and neuroendocrine cells, but it is unclear how this specialized organelle is formed and acquires its specific cargos. To identify proteins that act in dense-core vesicle biogenesis, we performed a forward genetic screen in Caenorhabditis elegans for mutants defective in dense-core vesicle function. We previously reported the identification of two conserved proteins that interact with the small GTPase RAB-2 to control normal dense-core vesicle cargo-sorting. Here we identify several additional conserved factors important for dense-core vesicle cargo sorting: the WD40 domain protein EIPR-1 and the endosome-associated recycling protein (EARP) complex. By assaying behavior and the trafficking of dense-core vesicle cargos, we show that mutants that lack EIPR-1 or EARP have defects in dense-core vesicle cargo-sorting similar to those of mutants in the RAB-2 pathway. Genetic epistasis data indicate that RAB-2, EIPR-1 and EARP function in a common pathway. In addition, using a proteomic approach in rat insulinoma cells, we show that EIPR-1 physically interacts with the EARP complex. Our data suggest that EIPR-1 is a new interactor of the EARP complex and that dense-core vesicle cargo sorting depends on the EARP-dependent trafficking of cargo through an endosomal sorting compartment.
Highlights
The dense-core vesicle is a specialized secretory organelle found in neurons and endocrine cells
Molecules stored in dense-core vesicles include peptide hormones like insulin and small molecule neurotransmitters like dopamine
We show that EIPR-1 physically and genetically interacts with the endosome-associated recycling protein (EARP) complex
Summary
The dense-core vesicle is a specialized secretory organelle found in neurons and endocrine cells. Two general models of dense-core vesicle cargo sorting have been debated for more than twenty years: the ‘sorting by entry’ and ‘sorting by retention’ models that propose that sorting occurs in the trans-Golgi as dense-core vesicles bud off (sorting by entry), or in a post-Golgi step where non-dense-core vesicle cargos are removed (sorting by retention) [15,16]. Experimental evidence supports both models, which are not mutually exclusive, suggesting that both mechanisms contribute to dense-core vesicle biogenesis
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