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 <i>VPS41</i> in mouse pancreatic β cells results in diabetes, although the mechanisms are not understood. Presently, we show that <i>VPS41</i> deletion results in rapid mature insulin degradation and downregulation of β-cell identity. This phenotype is observed in vivo, with <i>VPS41</i>KO mice displaying progressive loss of insulin content and β-cell function with age. In acute <i>VPS41</i> 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 <i>PDX1</i> and <i>INS</i> 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.<b>NEW & NOTEWORTHY</b> In this study, we show that acute <i>VPS41</i> deletion results in rapid degradation of insulin, whereas chronic <i>VPS41</i> deletion results in downregulation of β-cell identity. In acute <i>VPS41</i> 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 <i>PDX1</i> and <i>INS</i> mRNA expression. Inhibition of lysosomal degradation rescues the rapidly depleted insulin content.