AP-3 complex sorts preferential cargo to govern dense core vesicle function in neuroendocrine cells

This study reveals the multifaceted role of the adaptor protein (AP-3) complex in the function of dense-core vesicles (DCVs). Despite numerous studies, an existing lack of knowledge concerning the role of AP-3 in DCV function prompted us to delve deeper. Biochemical analysis revealed compromised DCV exocytosis in AP-3-depleted PC12 cells. AP-3 depletion altered the size and positioning of DCVs. Golgi defects and RUSH (retention using selective hook) substantiated the role of AP-3 in trans-Golgi DCV sorting. Proteomics analysis of cellular fractions revealed that AP-3 depleted cells showed the loss of specific DCV proteins, accompanied by mislocalization and rerouting to lysosomes. Bioinformatics and proximity ligation assays revealed interactions of mislocalized proteins with the AP-3 subunit. These findings corroborated functional defects in granule maturation, release modes, zinc, and neurotransmitter mobilization. Our study demonstrates multifaceted roles of the AP-3 complex in governing DCV function, thereby enabling us to understand neurotransmitter and neuropeptide release.