Self-Assembly of VPS41 Promotes Sorting Required for Biogenesis of the Regulated Secretory Pathway

•Regulated polypeptide secretion requires HOPS subunit VPS41•HOPS-independent role for VPS41 in regulated secretion depends on AP-3•VPS41 self-assembles into a lattice•Formation of the regulated secretory pathway depends on the self-assembly of VPS41

SummaryThe regulated release of polypeptides has a central role in physiology, behavior, and development, but the mechanisms responsible for production of the large dense core vesicles (LDCVs) capable of regulated release have remained poorly understood. Recent work has implicated cytosolic adaptor protein AP-3 in the recruitment of LDCV membrane proteins that confer regulated release. However, AP-3 in mammals has been considered to function in the endolysosomal pathway and in the biosynthetic pathway only in yeast. We now find that the mammalian homolog of yeast VPS41, a member of the homotypic fusion and vacuole protein sorting (HOPS) complex that delivers biosynthetic cargo to the endocytic pathway in yeast, promotes LDCV formation through a common mechanism with AP-3, indicating a conserved role for these proteins in the biosynthetic pathway. VPS41 also self-assembles into a lattice, suggesting that it acts as a coat protein for AP-3 in formation of the regulated secretory pathway.