VPS41 deletion triggers progressive loss of insulin stores and downregulation of beta-cell identity

Abstract

Vacuolar protein sorting-associated protein 41 (VPS41) has been established as a requirement for normal insulin secretory function in pancreatic beta-cells. Genetic deletion of VPS41 in mouse pancreatic beta-cells results in diabetes, though the mechanisms are not understood. Presently, we show that VPS41 deletion results in rapid mature insulin degradation and downregulation of beta-cell identity. This phenotype is observed in vivo, with VPS41KO mice displaying progressive loss of insulin content and beta-cell function with age. In acute VPS41 depletion in vitro, the loss of insulin is associated with increased degradative pathway activity, increased Adapter Protein 3 complex colocalisation with lysosomes, increased nuclear localisation of transcription factor E3, and downregulation of PDX1 and INS mRNA expression. Inhibition of lysosomal degradation rescues the rapidly depleted insulin content. These data evidence a VPS41-dependent mechanism for both insulin content degradation and loss of beta-cell identity in beta-cells.