Regulation of Insulin Granule Turnover in Pancreatic β-Cells by Cleaved ICA512
Regulation of Insulin Granule Turnover in Pancreatic β-Cells by Cleaved ICA512
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DOI：
10.1074/jbc.m804928200
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发表时间：
2008-11-28
影响因子：
4.8
通讯作者：
Solimena, Michele
中科院分区：
文献类型：
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作者：
Trajkovski, Mirko;Mziaut, Hassan;Solimena, Michele
胰岛素通过促进血液中的细胞摄取葡萄糖来维持葡萄糖的稳态。高血糖会触发胰腺β细胞分泌胰岛素。该过程由分泌颗粒胞吐作用介导。然而，β细胞如何保持颗粒储存相对恒定仍然未知。 ICA512 是一种内在的颗粒膜蛋白，其胞质结构域结合 β2-肌营养蛋白（一种 F-肌动蛋白相关蛋白），并在颗粒胞吐作用时被切割。由此产生的裂解胞质片段 ICA512-CCF 到达细胞核并上调颗粒基因（包括胰岛素和 ICA512）的转录。在这里，我们发现 ICA512-CCF 也与颗粒上完整的 ICA512 二聚化，从而将其从 β2-肌营养不良蛋白中取代。这导致颗粒流动性和胰岛素释放增加。基于这些发现，我们提出了一个模型，ICA512-CCF的产生首先放大胰岛素分泌。随后颗粒储存的减少将增加新生成的 ICA512-CCF 到达细胞核并增强颗粒生物发生的可能性，从而允许 β 细胞不断调整颗粒的生产以适应其储存大小和消耗。这些反馈回路的药理学调节可以缓解糖尿病中胰岛素释放不足的情况。
Insulin maintains homeostasis of glucose by promoting its uptake into cells from the blood. Hyperglycemia triggers secretion of insulin from pancreatic beta-cells. This process is mediated by secretory granule exocytosis. However, how beta-cells keep granule stores relatively constant is still unknown. ICA512 is an intrinsic granule membrane protein, whose cytosolic domain binds beta 2-syntrophin, an F-actin-associated protein, and is cleaved upon granule exocytosis. The resulting cleaved cytosolic fragment, ICA512-CCF, reaches the nucleus and up-regulates the transcription of granule genes, including insulin and ICA512. Here, we show that ICA512-CCF also dimerizes with intact ICA512 on granules, thereby displacing it from beta 2-syntrophin. This leads to increased granule mobility and insulin release. Based on these findings, we propose a model whereby the generation of ICA512-CCF first amplifies insulin secretion. The ensuing reduction of granule stores would then increase the probability of newly generated ICA512-CCF to reach the nucleus and enhance granule biogenesis, thus allowing beta-cells to constantly adjust production of granules to their storage size and consumption. Pharmacological modulation of these feedback loops may alleviate deficient insulin release in diabetes.