Polyadenylation of insulin mRNA by Tent5a regulates pancreatic beta cells

Pancreatic beta cells can compensate for increased metabolic demand by increasing their function. While many studies have investigated mechanisms of beta cell decompensation during persistent metabolic stress, less is known how beta cells increase insulin synthesis and secretion. Here we identify the non-canonical cytoplasmic terminal nucleotidyltransferase Tent5a in a functional RNAi screen of RNA binding proteins as a positive regulator of insulin production. Tent5a expression positively correlates with obese and normoglycemic mouse models exhibiting compensated beta cell function, while its levels negatively correlate with beta cell failure. Increased Tent5a expression can be triggered by ribosome collisions and is repressed by ER stress and lipotoxic inflammation. Tent5a overexpression extended the poly(A) tails of insulin transcripts, enhanced mRNA stability and increased insulin content in INS-1E cells and human islets microtissues, while Tent5a knockout cells showed shortened Insulin mRNA half-life and reduced insulin content. Cytosolic polyadenylation activity is dependent on Tent5a tethering to the endoplasmic reticulum (ER) via Fndc3 proteins, leading to increased ER function. Our data identify a role of Tent5a in enhancing insulin production, which may be involved in boosting insulin synthesis and maintaining euglycemia in obesity.