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Multiple Sorting Systems for Secretory Granules Ensure the Regulated Secretion of Peptide Hormones
Authors:Meng Sun  Tsuyoshi Watanabe  Hiroki Bochimoto  Yuko Sakai  Seiji Torii  Toshiyuki Takeuchi  Masahiro Hosaka
Affiliation:1. Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, , Maebashi, 371‐8512 Japan;2. Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, , Asahikawa, 078‐8510 Japan;3. Administration Office, Gunma University, , Maebashi, 371‐8510 Japan;4. Laboratory of Molecular Life Sciences, Department of Biotechnology, Akita Prefectural University, , Akita, 010‐0195 Japan
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.
Keywords:cholesterol  chromogranin A  peptide hormones  prohormone sorting  secretogranin II  secretogranin III  secretory granule
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