Exophilin-8 assembles secretory granules for exocytosis in the actin cortex via interaction with RIM-BP2 and myosin-VIIa
Fushun Fan,
Kohichi Matsunaga,
Hao Wang,
Ray Ishizaki,
Eri Kobayashi,
Hiroshi Kiyonari,
Yoshiko Mukumoto,
Katsuhide Okunishi,
Tetsuro Izumi
Affiliations
Fushun Fan
Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
Kohichi Matsunaga
Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
Hao Wang
Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
Ray Ishizaki
Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
Eri Kobayashi
Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
Hiroshi Kiyonari
Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, Japan; Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan
Yoshiko Mukumoto
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan
Katsuhide Okunishi
Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan; Research Program for Signal Transduction, Division of Endocrinology, Metabolism and Signal Research, Gunma University Initiative for Advanced Research, Maebashi, Japan
Exophilin-8 has been reported to play a role in anchoring secretory granules within the actin cortex, due to its direct binding activities to Rab27 on the granule membrane and to F-actin and its motor protein, myosin-Va. Here, we show that exophilin-8 accumulates granules in the cortical F-actin network not by direct interaction with myosin-Va, but by indirect interaction with a specific form of myosin-VIIa through its previously unknown binding partner, RIM-BP2. RIM-BP2 also associates with exocytic machinery, Cav1.3, RIM, and Munc13-1. Disruption of the exophilin-8–RIM-BP2–myosin-VIIa complex by ablation or knockdown of each component markedly decreases both the peripheral accumulation and exocytosis of granules. Furthermore, exophilin-8-null mouse pancreatic islets lose polarized granule localization at the β-cell periphery and exhibit impaired insulin secretion. This newly identified complex acts as a physical and functional scaffold and provides a mechanism supporting a releasable pool of granules within the F-actin network beneath the plasma membrane.
