The BAR Domain Protein Arfaptin-1 Controls Secretory Granule Biogenesis at the trans-Golgi Network
The BAR Domain Protein Arfaptin-1 Controls Secretory Granule Biogenesis at the trans-Golgi Network
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DOI：
10.1016/j.devcel.2012.07.019
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发表时间：
2012-10-16
影响因子：
11.8
通讯作者：
Ricci, Romeo
中科院分区：
文献类型：
--
作者：
Gehart, Helmuth;Goginashvili, Alexander;Ricci, Romeo
BAR结构域可以通过保护萌芽小泡的颈部免受分裂诱导因素的影响来防止膜分裂。然而，这种抑制功能及其调节的生理作用是未知的。在这里，我们确定了一个检查点，涉及BAR结构域的蛋白Arfaptin-1，控制在trans-Golgi网络（TGN）的分泌颗粒的生物发生。我们证明，蛋白激酶D（PKD）磷酸化Arfaptin-1在丝氨酸132，这破坏了Arfaptin-1抑制ADP核糖基化因子，囊泡切割机械的重要组成部分的活性的能力。这种调节机制的生理意义通过在表达非磷酸化Arfaptin-1的胰腺β细胞中由于颗粒断裂缺陷而导致的葡萄糖刺激的胰岛素分泌的损失来证明。因此，Arfaptin-1的消耗导致产生小的非功能性分泌颗粒。因此，PKD介导的Arfaptin-1磷酸化是必要的，以确保在调节分泌的TGN的功能性运输载体的生物合成。
BAR domains can prevent membrane fission through their ability to shield necks of budding vesicles from fission-inducing factors. However, the physiological role of this inhibitory function and its regulation is unknown. Here we identify a checkpoint involving the BAR-domain-containing protein Arfaptin-1 that controls biogenesis of secretory granules at the trans-Golgi network (TGN). We demonstrate that protein kinase D (PKD) phosphorylates Arfaptin-1 at serine 132, which disrupts the ability of Arfaptin-1 to inhibit the activity of ADP ribosylation factor, an important component of the vesicle scission machinery. The physiological significance of this regulatory mechanism is evidenced by loss of glucose-stimulated insulin secretion due to granule scission defects in pancreatic beta cells expressing nonphosphorylatable Arfaptin-1. Accordingly, depletion of Arfaptin-1 leads to the generation of small nonfunctional secretory granules. Hence, PKD-mediated Arfaptin-1 phosphorylation is necessary to ensure biogenesis of functional transport carriers at the TGN in regulated secretion.