Novel Roles of PACS-1 Within the Nucleus and the Regulated Secretory Pathway
Abstract
PACS-1 functions are explored in three linked sections: the investigation of PACS-1 nuclear trafficking, the impact of PACS-1 on calcium homeostasis, and PACS-1 regulation of membrane protein trafficking within the regulated secretory pathway. First, our results establish PACS-1 motifs that regulate nuclear localization through the classical nuclear trafficking pathway. Moreover, we have identified a novel interaction between PACS-1 and the nucleocytoplasmic RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1), unveiling a PACS-1 nuclear trafficking function. Second, we defined a role for PACS-1 orchestrating intracellular calcium levels within corticotropic cells. We establish PACS-1 interactions with transient receptor potential cation channel 3 subfamily C (TRPC3) and extended synaptotagmin 1 (ESyt-1), demonstrating that PACS-1 controls the trafficking of these proteins to the plasma membrane. Furthermore, we identify ESyt-1 as a negative regulator of adrenocorticotropic hormone (ACTH) secretion that requires PACS-1 to complete this regulation. Third, we elucidated adaptor protein complex 1 (AP-1) residues that interact with PACS-1. We further demonstrate that PACS-1 interacts with the ACTH processing enzyme peptidylglycine alpha-amidating monooxygenase (PAM) and is required for sorting PAM into the regulated secretory pathway in corticotropic cells. In conclusion, this research significantly advances our understanding of PACS-1's diverse functions within cells. By identifying trafficking functions for PACS-1 within nucleocytoplasmic shuttling, membrane trafficking of calcium ion channels, and retaining essential prohormone processing proteins within the regulated secretory pathway, this research truly underscores the multifunctional roles PACS-1 executes to maintain cellular homeostasis.