Login | Register

Selective Polytopic Protein Degradation by Organelle Membrane Fusion

Title:

Selective Polytopic Protein Degradation by Organelle Membrane Fusion

McNally, Erin K (2017) Selective Polytopic Protein Degradation by Organelle Membrane Fusion. PhD thesis, Concordia University.

[thumbnail of McNally_PhD_F2017.pdf]
Preview
Text (application/pdf)
McNally_PhD_F2017.pdf - Accepted Version
35MB

Video (video/mp4)
MovieS1.mp4 - Accepted Version
1MB

Video (video/mp4)
MovieS2.mp4 - Accepted Version
542kB

Video (video/mp4)
MovieS3.mp4 - Accepted Version
407kB

Video (video/mp4)
MovieS4.mp4 - Accepted Version
601kB

Video (video/mp4)
MovieS5.mp4 - Accepted Version
523kB

Video (video/mp4)
MovieS6.mp4 - Accepted Version
230kB

Video (video/mp4)
MovieS7.mp4 - Accepted Version
506kB

Video (video/mp4)
MovieS8.mp4 - Accepted Version
1MB

Video (video/mp4)
MovieS9.mp4 - Accepted Version
708kB

Video (video/mp4)
MovieS10.mp4 - Accepted Version
502kB

Video (video/mp4)
MovieS11.mp4 - Accepted Version
655kB

Video (video/mp4)
MovieS12.mp4 - Accepted Version
417kB

Video (video/mp4)
MovieS13.mp4 - Accepted Version
355kB

Video (video/mp4)
MovieS14.mp4 - Accepted Version
267kB

Video (video/mp4)
MovieS15.mp4 - Accepted Version
326kB

Video (video/mp4)
MovieS16.mp4 - Accepted Version
318kB

Video (video/mp4)
MovieS17.mp4 - Accepted Version
408kB

Video (video/mp4)
MovieS18.mp4 - Accepted Version
449kB

Video (video/mp4)
MovieS19.mp4 - Accepted Version
293kB

Abstract

Lysosomes are dynamic organelles most notably known as the terminal compartments of the endocytic and autophagy pathways in eukaryotic cells. However, lysosome function is not simply for the elimination and catabolism of biomaterials. Rather lysosomes have emerged as critical and dynamic signaling hubs via their ability to sense and provide nutrients, and communicate this information to biosynthetic or metabolic processes. Lysosome physiology relies on membrane transporter activity, best signified by loss-of-function mutations linked to lysosomal storage disorders. These include nutrient transporter proteins that export products of catabolism to the cytoplasm for cellular reuse, as well as Ca2+ pumps and transporters important for signaling, and transporters for metal storage and homeostasis. Eukaryotic cells, and their lysosomes, undergo continuous renovation to clear damaged or unused proteins or to alter their proteome accommodating functional changes in response to the environment, physiological cues, or aging. Despite the importance of lysosomal transporters to cell physiology, little is known about their lifetimes and it remains unclear how they are degraded.
Here, I used Saccharomyces cerevisiae and its vacuolar lysosome as models to study lysosomal transporter lifetimes and discovered a new cellular protein degradation pathway, the IntraLumenal Fragment (ILF) pathway: During membrane fusion events between lysosomes, transporters are selectively labeled for recognition and sorting by the fusion protein machinery into an area of membrane spanning the apposed organelles. Upon fusion, this membrane and proteins embedded within it are internalized into the lumen as a byproduct for degradation by hydrolases. I find the ILF pathway selectively degrades lysosomal transporters when misfolded, in response to TOR signaling or changes in substrate levels. I also find that protein clients are not limited to lysosomal transporters, as this pathway degrades internalized surface membrane proteins that bypass entry into the canonical MultiVesicular Body pathway, which was previously thought to be the exclusive mechanism for selective surface protein degradation. Finally, I find the ILF pathway cooperates with a second, independent protein degradation pathway, the vReD pathway, to change the lysosomal membrane proteome. The underlying machinery and transporters studied are evolutionarily conserved, suggesting the ILF pathway contributes to lysosome physiology in all eukaryotic cells.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Thesis (PhD)
Authors:McNally, Erin K
Institution:Concordia University
Degree Name:Ph. D.
Program:Biology
Date:25 August 2017
Thesis Supervisor(s):Brett, Christopher
ID Code:982854
Deposited By: ERIN MCNALLY
Deposited On:08 Nov 2017 20:29
Last Modified:18 Jan 2018 17:55
All items in Spectrum are protected by copyright, with all rights reserved. The use of items is governed by Spectrum's terms of access.

Repository Staff Only: item control page

Downloads per month over past year

Research related to the current document (at the CORE website)
- Research related to the current document (at the CORE website)
Back to top Back to top