EIPR1 controls dense-core vesicle cargo sorting and EARP complex localization in insulinoma cells

Dense-core vesicles (DCVs) are secretory vesicles found in neurons and endocrine cells. DCVs package and release cargos including neuropeptides, biogenic amines, and peptide hormones. We recently identified the endosome-associated recycling protein (EARP) complex and the EARP-interacting protein EIPR-1 as proteins important for DCV biogenesis in C. elegans neurons. Here we determine the role of mammalian EIPR1 in insulinoma cells. We find that in Eipr1 KO cells, mature DCV cargos such as insulin accumulate at the trans-Golgi network and there is reduced insulin secretion. In addition, we find that EIPR1 is required for the stability of the EARP complex subunits and for the localization of EARP and its association with membranes. EARP is localized to two distinct compartments related to its function: an endosomal compartment and a DCV-related compartment. We propose that EIPR1 functions with EARP to control both endocytic recycling and DCV cargo sorting.