title: Multiple sorting systems for secretory granules ensure the regulated secretion of peptide hormones.
abstract: Prior to secretion, regulated peptide hormones are selectively sorted to secretory granules (SGs) at the trans-Golgi network (TGN) in endocrine cells. Secretogranin III (SgIII) appears to facilitate SG sorting process by tethering of protein aggregates containing chromogranin A (CgA) and peptide hormones to the cholesterol-rich SG membrane (SGM). Here, we evaluated the role of SgIII in SG sorting in AtT-20 cells transfected with small interfering RNA targeting SgIII. In the SgIII-knockdown cells, the intracellular retention of CgA was greatly impaired, and only a trace amount of CgA was localized within the vacuoles formed in the TGN, confirming the significance of SgIII in both the tethering of CgA-containing aggregates and the establishment of the proper SG morphology. Although the intracellular retention of proopiomelanocortin (POMC) was considerably impaired in SgIII-knockdown cells, residual adrenocorticotropic hormone (ACTH)/POMC was still localized to some few remaining SGs together with another granin protein, secretogranin II (SgII), and was secreted in a regulated manner. Biochemical analyses indicated that SgII bound directly to the SGM in a cholesterol-dependent manner and was able to retain the aggregated form of POMC, revealing a latent redundancy in the SG sorting and retention mechanisms, that ensures the regulated secretion of bioactive peptides.
authors.affiliation: Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512, Japan.
authors.forename: Meng
authors.initials: M
authors.lastname: Sun
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hiroki
authors.initials: H
authors.lastname: Bochimoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sakai
authors.forename: Seiji
authors.initials: S
authors.lastname: Torii
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hosaka
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D053379:Chromogranin A / Q000378:metabolism; D002864:Chromogranins / Q000235:genetics / Q000378:metabolism; D005089:Exocytosis; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D016716:PC12 Cells; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering; D053381:Secretogranin II / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D014617:Vacuoles / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D053379:Chromogranin A; D002864:Chromogranins; D034741:RNA, Small Interfering; D053381:Secretogranin II; C506155:chromogranin A, mouse; C506138:secretogranin 2, mouse; C506139:secretogranin 3, mouse; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D002784:Cholesterol