Regulation of insulin granule turnover in pancreatic beta-cells by cleaved ICA512.
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.
Trajkovski
Mirko
M
Laboratory of Experimental Diabetology, School of Medicine, Dresden University of Technology, Dresden 01307, Germany.
Mziaut
Hassan
H
Schubert
Sandra
S
Kalaidzidis
Yannis
Y
Altkrüger
Anke
A
Solimena
Michele
M
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics; D049029:Dystrophin-Associated Proteins / Q000235:genetics / Q000378:metabolism; D005089:Exocytosis / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017434:Protein Structure, Tertiary / Q000235:genetics; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000235:genetics / Q000378:metabolism*; D022142:Secretory Vesicles / Q000235:genetics / Q000378:metabolism*
D049029:Dystrophin-Associated Proteins; D007328:Insulin; D008565:Membrane Proteins; C091824:syntrophin; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8