title: Rab2a and Rab27a cooperatively regulate the transition from granule maturation to exocytosis through the dual effector Noc2.
abstract: Exocytosis of secretory granules entails budding from the trans-Golgi network, sorting and maturation of cargo proteins, and trafficking and fusion to the plasma membrane. Rab27a regulates the late steps in this process, such as granule recruitment to the fusion site, whereas Rab2a functions in the early steps, such as granule biogenesis and maturation. Here, we demonstrate that these two small GTPases simultaneously bind to Noc2 (also known as RPH3AL) in a GTP-dependent manner, although Rab2a binds only after Rab27a has bound. In pancreatic β-cells, the ternary Rab2a-Noc2-Rab27a complex specifically localizes on perinuclear immature granules, whereas the binary Noc2-Rab27a complex localizes on peripheral mature granules. In contrast to the wild type, Noc2 mutants defective in binding to Rab2a or Rab27a fail to promote glucose-stimulated insulin secretion. Although knockdown of any component of the ternary complex markedly inhibits insulin secretion, only knockdown of Rab2a or Noc2, and not that of Rab27a, impairs cargo processing from proinsulin to insulin. These results suggest that the dual effector, Noc2, regulates the transition from Rab2a-mediated granule biogenesis to Rab27a-mediated granule exocytosis.
authors.affiliation: Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Kohichi
authors.initials: K
authors.lastname: Matsunaga
authors.affiliation: Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Taoka
authors.affiliation: Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Isobe
authors.affiliation: Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan tizumi@gunma-u.ac.jp.|Research Program for Signal Transduction, Division of Endocrinology, Metabolism and Signal Research, Gunma University Initiative for Advanced Research, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Tetsuro
authors.identifier: 0000-0002-0974-7384
authors.initials: T
authors.lastname: Izumi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D003594:Cytoplasmic Granules / Q000378:metabolism*; D005089:Exocytosis; D006160:Guanosine Triphosphate / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins; D020693:rab2 GTP-Binding Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006160:Guanosine Triphosphate; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D011506:Proteins; D020691:rab GTP-Binding Proteins; D000075745:rab27 GTP-Binding Proteins; C484660:Rph3al protein, mouse; C000602046:Rab2a protein, mouse; D020693:rab2 GTP-Binding Protein; C512962:Rab27a protein, mouse
keywords: Diabetes; Insulin; Pancreatic β-cell; Regulated exocytosis; Secretory granule; Small GTPase