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

Vacuolar protein sorting-associated protein 41 (VPS41) has been established as a requirement for normal insulin secretory function in pancreatic β cells. Genetic deletion of VPS41 in mouse pancreatic β cells results in diabetes, although the mechanisms are not understood. Presently, we show that VPS41 deletion results in rapid mature insulin degradation and downregulation of β-cell identity. This phenotype is observed in vivo, with VPS41KO mice displaying progressive loss of insulin content and β-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 colocalization with lysosomes, increased nuclear localization 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 β-cell identity in β cells.NEW & NOTEWORTHY In this study, we show that acute VPS41 deletion results in rapid degradation of insulin, whereas chronic VPS41 deletion results in downregulation of β-cell identity. In acute VPS41 depletion in vitro, the loss of insulin is associated with increased degradative pathway activity, increased Adapter Protein 3 complex colocalization with lysosomes, increased nuclear localization of transcription factor E3, and downregulation of PDX1 and INS mRNA expression. Inhibition of lysosomal degradation rescues the rapidly depleted insulin content.