Exophilin-8 assembles secretory granules for exocytosis in the actin cortex via interaction with RIM-BP2 and myosin-VIIa
Exophilin-8 assembles secretory granules for exocytosis in the actin cortex via interaction with RIM-BP2 and myosin-VIIa
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DOI：
10.7554/elife.26174
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发表时间：
2017-07-04
期刊：
影响因子：
7.7
通讯作者：
Izumi, Tetsuro
中科院分区：
文献类型：
--
作者：
Fan, Fushun;Matsunaga, Kohichi;Izumi, Tetsuro
据报道，由于其与颗粒膜上的Rab 27和F-肌动蛋白及其运动蛋白肌球蛋白-Va的直接结合活性，外泌素-8在肌动蛋白皮质内锚定分泌颗粒中起作用。在这里，我们表明，exophilin-8积累颗粒在皮质F-肌动蛋白网络不直接与肌球蛋白-Va的相互作用，但通过间接的相互作用与特定形式的肌球蛋白-Vila通过其以前未知的结合伙伴，RIM-BP 2。RIM-BP 2还与胞吐机制、Ca（v）1.3、RIM和Munc 13 -1相关。通过消融或敲低每种组分来破坏exophilin-8-RIM-BP 2肌球蛋白-VIIa复合物显著降低颗粒的外周积累和胞吐作用。此外，exophilin-8-null小鼠胰岛在β-细胞外周失去极化颗粒定位，并表现出受损的胰岛素分泌。这种新发现的复合物作为一种物理和功能支架，并提供了一种机制，支持质膜下的F-肌动蛋白网络内的可释放的颗粒池。
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-Vila through its previously unknown binding partner, RIM-BP2. RIM-BP2 also associates with exocytic machinery, Ca(v)1.3, 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 beta-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.