Insulin mRNA is stored in RNA granules in resting beta cells

The glucose-stimulated biosynthesis of insulin in pancreatic islet beta cells is post-transcriptionally regulated. Several RNA-binding proteins (RBPs) that regulate Insulin mRNA stability and translation also bind mRNAs coding for other insulin secretory granule (ISG) proteins. However, an overview of these interactions and their glucose-induced remodelling is still missing. Here we identify two distinct sets of RBPs that were preferentially pulled down with the 5-UTRs of mouse Ins1, Ins2, spliced Ins2, Ica512/Ptprn and Pc2/Pcsk2 mRNAs from extracts of either resting or stimulated mouse insulinoma MIN6 cells. Among RBPs binding to all tested transcripts in resting conditions was hnRNP A2/B1. Hnrnpa2b1 KO MIN6 cells contained lower levels of Ins1 mRNA, proinsulin and insulin, and had reduced insulin secretion. In resting cells, both hnRNP A2/B1 and Insulin mRNAs localized to stress granules, which dissolved upon glucose stimulation. Insulin mRNA-positive RNA granules were also found in human pancreatic beta cells in situ. Our results suggest that resting beta cells store mRNAs for insulin secretory granule proteins in stress granules through specific RNA protein interactions. Glucose stimulation remodels these interactions, releasing the transcripts, and another set of RBPs coordinates their translation.