Date of Award

1-1-2019

Document Type

Masters Thesis

Degree Name

M.S.

Organizational Unit

College of Natual Science and Mathematics, Biological Sciences

First Advisor

Cedric S. Asensio, Ph.D.

Keywords

Diabetes, HOPS, Homotypic fusion and vacuole protein sorting, 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.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Christian Henry Burns

Provenance

Received from ProQuest

File Format

application/pdf

Language

en

File Size

71 p.

Discipline

Cellular biology, Biochemistry, Endocrinology

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