Polyadenylation of Insulin mRNA by Tent5a regulates pancreatic beta cell function

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, much less is known how beta cells increase the synthesis and secretion of insulin. Here we identify the non-canonical cytoplasmic terminal nucleotidyl-transferase Tent5a in a functional RNAi screen of RNA binding proteins as a positive regulator of insulin production and secretion. 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. Increased Tent5a levels increased polyadenylation and extended poly(A) tails of insulin transcripts to enhance mRNA stability, leading to increased insulin content. Cytosolic polyadenylation activity is dependent on Tent5a tethering to the endoplasmic reticulum (ER) via FDNC proteins, leading to increased ER function. Our data reveal a role of Tent5a in enhancing insulin production as well as in the regulation cellular homeostasis via chaperoning and isomerization of insulin, which are required to boost insulin synthesis and maintain euglycemia in obesity.