Pancreatic beta-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

Abstract

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood.VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism. * *

Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1‐dependent TFEB/TFE3 regulation

“…Interestingly, we found that expression of VPS41 S285P fully rescued the secretion defect in VPS41 KO PC12 cells. Likewise, in a parallel study we found that expression of VPS41 S285P in VPS41 KO INS-1 cells restored insulin secretion (Burns et al, 2020). This shows that expression of VPS41 S285P fails to restore HOPS function, but does rescue the regulated secretion pathway in PC12 and INS cells.…”

“…In secretory cells, VPS41 is required for secretory protein sorting and secretory granule biogenesis in a pathway that is independent of the HOPS complex (Asensio et al, 2013;Burns et al, 2020). This VPS41 function requires the N-terminal residues 1-36 for interaction with AP-3 and the presence of the C-terminal located CHCR domain (Asensio et al, 2013;Margarita Cabrera et al, 2010).…”