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 in mouse pancreatic β cells results in diabetes, although the mechanisms are not understood. Presently, we show that deletion results in rapid mature insulin degradation and downregulation of β-cell identity. This phenotype is observed in vivo, with KO mice displaying progressive loss of insulin content and β-cell function with age. In acute 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 and 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. In this study, we show that acute deletion results in rapid degradation of insulin, whereas chronic deletion results in downregulation of β-cell identity. In acute 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 and mRNA expression. Inhibition of lysosomal degradation rescues the rapidly depleted insulin content.