Grubb, Sarah Renee
(2013)
CHARACTERIZATION OF FACTORS THAT IMPACT APOLIPOPROTEIN B
SECRETION AND ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Apolipoprotein B (ApoB) is a lipoprotein that transports cholesterol and triglycerides through the bloodstream. High plasma levels of ApoB are one of the strongest risk factors for the development of Coronary Artery Disease. Using a yeast expression system for ApoB, I focused my research on identifying new therapeutic targets to reduce the amount of ApoB secreted into the bloodstream. One way that ApoB levels are regulated is through Endoplasmic Reticulum-Associated Degradation (ERAD), a quality control mechanism that rids the secretory pathway of misfolded proteins. Due to ApoB’s hydrophobic character and high number of disulfide bonds, one class of proteins that I hypothesized may contribute to ApoB ERAD was the Protein
Disulfide Isomerase (PDI) family. PDI’s catalyze the oxidation, reduction, and isomerization of disulfide bonds and some also have chaperone-like activity. I found that in yeast, Pdi1 contributes to ApoB ERAD through its chaperone like domain. I identified mammalian PDI candidates that may similarly affect ApoB biogenesis based on my yeast data. I found that in hepatic cells, two PDI family members, ERp57 and ERp72, contribute to ApoB ERAD, while another family member, PDI, promoted ApoB secretion. A unique aspect of ApoB ERAD is that the protein is co-translationally retrotranslocated and degraded. I hypothesized that proteins that regulate the Sec61 translocon, a proteinacious channel that allows ApoB entrance to the ER as well as an exit to the cytoplasm for degradation, would contribute to ApoB retrotranslocation and degradation. I discovered that two conserved ER-membrane proteins that are candidates for Sec61 regulators, Yet2 and Yet3, facilitate the ERAD of ApoB in yeast. To determine whether my results are relevant in mammalian cells, I am currently working to determine if the mammalian homologs of Yet2 and Yet3, BAP29 and BAP31 facilitate ApoB ERAD in hepatic cells.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
30 June 2013 |
| Date Type: |
Publication |
| Defense Date: |
9 November 2012 |
| Approval Date: |
30 June 2013 |
| Submission Date: |
8 February 2013 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
195 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Biological Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Apolipoprotein B, Protein Disulfide Isomerase, Endoplasmic Reticulum-Associated Degradation |
| Date Deposited: |
30 Jun 2013 19:42 |
| Last Modified: |
30 Jun 2018 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/17303 |
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