Journal
JOURNAL OF CELL SCIENCE
Volume 118, Issue 20, Pages 4785-4795Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.02608
Keywords
secretogranin III; carboxypeptidase E; chromogranin A; proopiomelanocortin; prohormone sorting
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Secretogranin III (SgIII) and carboxypeptidase E (CPE) bind specifically to cholesterol-rich secretory granule (SG) membranes. We previously showed that SgIII binds chromogranin A (CgA) and targets CgA to the SGs in endocrine cells. We investigated the binding of SgIII and CPE because they frequently localize close to the periphery of SGs, and they bind each other in mouse corticotrope-derived AtT-20 cells. In Cpe(fat) mouse corticotropes, which have defective CPE, proopiomelanocortin (POMC)-derived adrenocorticotrophin hormone (ACTH)-containing peptides were distributed over the entire surface of the SGs, and displayed a regulated secretion by secretagogues. The Cpe(fat) pituitary exhibited elevated levels of SgIII and CgA, which suggests that they compensate for a sorting function of CPE for POMC and its intermediates to ACTH. Indeed, both SgIII and CgA were able to bind POMC-derived intermediates. In a competitive pull-down assay, excessive SgIII led to a decrease in CPE-bound POMC-derived intermediate molecules, and SgIII pulled-down by anti-ACTH antibody increased proportionately. We suggest that SgIII and CPE form the separate functional sorting complex by anchoring to cholesterol-rich SG membranes, and PONIC-derived peptides are transferred from CPE to SgIII, and subsequently to CgA.
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