PACS-1 and adaptor protein-1 mediate ACTH trafficking to the regulated secretory pathway

Highlights: • PACS-1 and AP-1 play critical roles in targeting ACTH to the regulated secretory pathway. • PACS-1 and AP-1 promote the intracellular storage of ACTH. • In the absence of PACS-1 and AP-1, ACTH is constitutively secreted. • PACS-1 localizes to ACTH-positive vesicles in an AP-1-dependent manner. The regulated secretory pathway is a specialized form of protein secretion found in endocrine and neuroendocrine cell types. Pro-opiomelanocortin (POMC) is a pro-hormone that utilizes this pathway to be trafficked to dense core secretory granules (DCSGs). Within this organelle, POMC is processed to multiple bioactive hormones that play key roles in cellular physiology. However, the complete set of cellular membrane trafficking proteins that mediate the correct sorting of POMC to DCSGs remain unknown. Here, we report the roles of the phosphofurin acidic cluster sorting protein – 1 (PACS-1) and the clathrin adaptor protein 1 (AP-1) in the targeting of POMC to DCSGs. Upon knockdown of PACS-1 and AP-1, POMC is readily secreted into the extracellular milieu and fails to be targeted to DCSGs.