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Regulation of insulin granule turnover in pancreatic ß-cells by cleaved ICA512

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Trajkovski,  Mirko
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

Schubert,  Sandra
Max Planck Society;

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Kalaidzidis,  Yannis
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

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Solimena,  Michele
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

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Citation

Trajkovski, M., Mziaut, H., Schubert, S., Kalaidzidis, Y., Altkrüger, A., & Solimena, M. (2008). Regulation of insulin granule turnover in pancreatic ß-cells by cleaved ICA512. Journal of Biological Chemistry, 283(48), 33719-33729.


Cite as: https://hdl.handle.net/21.11116/0000-0001-0E7D-5
Abstract
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 beta2-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 beta2-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.