Date of Award
Cedric S. Asensio
Diabetes, HOPS, Insulin, Lysosome, Regulated Secretion, VPS41
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 membrane 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
endolysosomal tethering HOPS complex, was recently identified as a cytosolic factor
involved in the formation of neuroendocrine/neuronal granules. We now find that a stable
pool of VPS41 exists outside of HOPS and is required for regulated insulin secretion.
Loss of VPS41 leads to a reduction in insulin SG number and changes in their
transmembrane protein composition, associated with defects in granule release properties.
We further show that a human point mutation, identified in patients with neurological
defects but no endocrine defects, enables isolation of the HOPS independent function of
VPS41. Finally, we report that mice with a deletion of VPS41 specifically in Î²-cells
develop a diabetic phenotype due to a defect in insulin secretion. Altogether our data
suggest that VPS41 contributes significantly to glucose homeostasis.
Burns, Christian Henry, "Characterization of VPS41 and its Role in the Regulated Secretory Pathway" (2019). Electronic Theses and Dissertations. 1567.
Recieved from ProQuest
Christian Henry Burns
Cellular biology, Biochemistry, Endocrinology