Argonaute2 regulates the pancreatic β-cell secretome

Argonaute2 (Ago2) is an established component of the microRNA-induced silencing complex. Similar to miR-375 loss-of-function studies, inhibition of Ago2 in the pancreatic beta-cell resulted in enhanced insulin release underlining the relationship between these two genes. Moreover, as the most abundant microRNA in pancreatic endocrine cells, miR-375 was also observed to be enriched in Ago2-associated complexes. Both Ago2 and miR-375 regulate the pancreatic beta-cell secretome and we identified using quantitative mass spectrometry the enhanced release of a set of proteins or secretion signature in response to a glucose stimulus using the murine beta-cell line, MIN6. In addition, loss of Ago2 resulted in the increased expression of miR-375 target genes, including gephyrin and ywhaz. These targets positively contribute to exocytosis indicating they may mediate the functional role of both miR-375 and Ago proteins in the pancreatic beta-cell by influencing the secretory pathway. This study specifically addresses the role of Ago2 in the systemic release of proteins from beta-cells and highlights the contribution of the microRNA pathway to the function of this cell type.