CCDC186 recruits EARP and controls dense-core vesicle cargo sorting by exit

ABSTRACT The regulated release of peptide hormones depends on their packaging into dense-core vesicles (DCVs). Two models have been proposed for DCV cargo sorting. The “sorting by entry” model proposes that DCV cargos selectively enter nascent DCVs at the trans-Golgi network (TGN). The “sorting by exit” model proposes that sorting occurs by the post-TGN removal of non-DCV cargos and retention of mature DCV cargos. Here we show that the coiled-coil protein CCDC186 controls sorting by exit. Ccdc186 KO insulinoma cells secrete less insulin, fail to retain insulin and carboxypeptidase E in mature DCVs at the cell periphery, and fail to remove carboxypeptidase D from immature DCVs. A mutation affecting the endosome-associated recycling protein (EARP) complex causes similar defects in DCV cargo sorting, and overexpression of CCDC186 recruits EARP to the site of DCV maturation. CCDC186 and EARP may act together to control the post-Golgi retention of cargos in mature DCVs.