The EARP Complex and Its Interactor EIPR-1 Are Required for Cargo Sorting to Dense-Core Vesicles

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. © 2016 topalidou et al.