The Rab27a effector exophilin7 promotes fusion of secretory granules that have not been docked to the plasma membrane

H Wang, R Ishizaki, J Xu, K Kasai… - Molecular Biology of …, 2013 - Am Soc Cell Biol
H Wang, R Ishizaki, J Xu, K Kasai, E Kobayashi, H Gomi, T Izumi
Molecular Biology of the Cell, 2013Am Soc Cell Biol
Granuphilin, an effector of the small GTPase Rab27a, mediates the stable attachment
(docking) of insulin granules to the plasma membrane and inhibits subsequent fusion of
docked granules, possibly through interaction with a fusion-inhibitory Munc18-1/syntaxin
complex. However, phenotypes of insulin exocytosis differ considerably between Rab27a-
and granuphilin-deficient pancreatic β cells, suggesting that other Rab27a effectors function
in those cells. We found that one of the putative Rab27a effector family proteins …
Granuphilin, an effector of the small GTPase Rab27a, mediates the stable attachment (docking) of insulin granules to the plasma membrane and inhibits subsequent fusion of docked granules, possibly through interaction with a fusion-inhibitory Munc18-1/syntaxin complex. However, phenotypes of insulin exocytosis differ considerably between Rab27a- and granuphilin-deficient pancreatic β cells, suggesting that other Rab27a effectors function in those cells. We found that one of the putative Rab27a effector family proteins, exophilin7/JFC1/Slp1, is expressed in β cells; however, unlike granuphilin, exophilin7 overexpressed in the β-cell line MIN6 failed to show granule-docking or fusion-inhibitory activity. Furthermore, exophilin7 has no affinities to either Munc18-1 or Munc18-1–interacting syntaxin-1a, in contrast to granuphilin. Although β cells of exophilin7-knockout mice show no apparent abnormalities in intracellular distribution or in ordinary glucose-induced exocytosis of insulin granules, they do show impaired fusion in response to some stronger stimuli, specifically from granules that have not been docked to the plasma membrane. Exophilin7 appears to mediate the fusion of undocked granules through the affinity of its C2A domain toward the plasma membrane phospholipids. These findings indicate that the two Rab27a effectors, granuphilin and exophilin7, differentially regulate the exocytosis of either stably or minimally docked granules, respectively.
Am Soc Cell Biol