Role of the Interaction Between Nck1 and PERK in Pancreatic Beta Cell Function and Survival

Abstract

Preventing pancreatic β cell failure and death, features of diabetes pathogenesis, could help treat diabetes. PERK, a player in the unfolded protein response (UPR), is essential for β cell function and survival. We have shown that PERK, when residue Y561 is phosphorylated, is bound and regulated by the adaptor protein Nck1 (non-catalytic region of tyrosine kinase adaptor protein 1). Silencing Nck1 in β cells enhances basal PERK activity and prevents its hyperactivation under gluco-lipotoxic conditions, improving proinsulin synthesis and β cell survival. Our preliminary results also showed that islet grafts lacking Nck1 perform better compared to WT grafts to reverse streptozotocin-induced diabetes in mice. Thus, we hypothesize that disruption of the specific Nck1/PERK interaction could improve β cell health and generate a phosphopeptide (TAT-pY561) that sequesters Nck1 and prevents its interaction with PERK. As predicted, this peptide increases insulin synthesis and decreases apoptosis in cultured beta cells under gluco-lipotoxic conditions. In vivo, the peptide administered daily for 3 weeks to mice (prior to and during induction of diabetes using HFD + streptozotocin) increased pancreatic insulin content and glucose-stimulated insulin secretion compared to vehicle treated mice. Moreover, in human diabetic islets, in vitro treatment with the peptide tended to increase insulin content. Our data suggest that inhibition of Nck1/PERK interaction, in mouse and human islets, improves β cell survival and function. Targeting this interaction might prove useful to enhance beta cell health in diabetes and/or when producing sources of beta cells for transplantation.