Date of Award

1-1-2019

Document Type

Thesis

Degree Name

M.S.

Department

Biological Sciences

First Advisor

Cedric S. Asensio

Keywords

Diabetes, HOPS, Insulin, Lysosome, Regulated Secretion, VPS41

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 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 β-cells

develop a diabetic phenotype due to a defect in insulin secretion. Altogether our data

suggest that VPS41 contributes significantly to glucose homeostasis.

Provenance

Recieved from ProQuest

Rights holder

Christian Henry Burns

File size

71 p.

File format

application/pdf

Language

en

Discipline

Cellular biology, Biochemistry, Endocrinology

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