Regulation of the expression of components of the exocytotic machinery of insulin-secreting cells by microRNAs.
Fine-tuning of insulin secretion from pancreatic beta-cells participates in blood glucose homeostasis. Defects in this process can lead to chronic hyperglycemia and diabetes mellitus. Several proteins controlling insulin exocytosis have been identified, but the mechanisms regulating their expression remain poorly understood. Here, we show that two non-coding microRNAs, miR124a and miR96, modulate the expression of proteins involved in insulin exocytosis and affect secretion of the beta-cell line MIN6B1. miR124a increases the levels of SNAP25, Rab3A and synapsin-1A and decreases those of Rab27A and Noc2. Inhibition of Rab27A expression is mediated by direct binding to the 3'-untranslated region of Rab27A mRNA. The effect on the other genes is indirect and linked to changes in mRNA levels. Over-expression of miR124a leads to exaggerated hormone release under basal conditions and a reduction in glucose-induced secretion. miR96 increases mRNA and protein levels of granuphilin, a negative modulator of insulin exocytosis, and decreases the expression of Noc2, resulting in lower capacity of MIN6B1 cells to respond to secretagogues. Our data identify miR124a and miR96 as novel regulators of the expression of proteins playing a critical role in insulin exocytosis and in the release of other hormones and neurotransmitters.
Lovis
Pascal
P
Department of Cell Biology and Morphology, Faculty of Biology and Medicine, University of Lausanne, CH-1005 Lausanne, Switzerland.
Gattesco
Sonia
S
Regazzi
Romano
R
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins; D020826:rab3A GTP-Binding Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D011506:Proteins; C484660:Rph3al protein, mouse; D016704:Synapsins; D050825:Synaptosomal-Associated Protein 25; C122015:Sytl4 protein, mouse; D033921:Vesicular Transport Proteins; D000075745:rab27 GTP-Binding Proteins; D005576:Colforsin; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins; D020826:rab3A GTP-Binding Protein; D005947:Glucose; D015056:1-Methyl-3-isobutylxanthine