Scott, Craig McNary
(2007)
ADD66, A GENE REQUIRED FOR THE ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION (ERAD) OF ALPHA-1-ANTITRYPSIN-Z IN YEAST, FACILITATES PROTEASOME ACTIVITY AND ASSEMBLY.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Antitrypsin Deficiency is a primary cause of juvenile liver disease and arises from expression of the "Z" variant of the alpha-1 protease inhibitor (A1Pi). Whereas A1Pi is secreted from the liver, A1PiZ is retro-translocated from the endoplasmic reticulum (ER) and degraded by the proteasome, an event that may offset liver damage. To better define the mechanism of A1PiZ degradation, a yeast expression system was developed and a gene, ADD66, was identified that facilitates A1PiZ turn-over. I report here that ADD66 encodes an ~30 kDa soluble, cytosolic protein and that the chymotrypsin-like activity of the proteasome is reduced in add66Ä mutants. This reduction in activity may arise from the accumulation of 20S proteasome assembly intermediates or from qualitative differences in assembled proteasomes. Add66p also appears to be a proteasome substrate. Consistent with its role in ER associated degradation (ERAD), synthetic interactions are observed between the genes encoding Add66p and Ire1p, a transducer of the unfolded protein response, and yeast deleted for both ADD66 and/or IRE1 accumulate polyubiquitinated proteins. These data identify Add66p as a proteasome assembly chaperone (PAC) and provide the first link between PAC activity and ERAD.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Scott, Craig McNary | crs7@pitt.edu | CRS7 | |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Chair | Brodsky, Jeffrey | jbrodsky@pitt.edu | JBRODSKY | | | Committee Member | Apodaca, Gerard | | | | | Committee Member | Hatfull, Grahm | | | | | Committee Member | Arndt, Karen | | | | | Committee Member | Gilbert, Susan | | | |
|
| Date: |
19 September 2007 |
| Date Type: |
Completion |
| Defense Date: |
29 June 2007 |
| Approval Date: |
19 September 2007 |
| Submission Date: |
10 July 2007 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| 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: |
chaperone; PAC2; Pba2; unfolded protein response; UPR |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-07102007-113926/, etd-07102007-113926 |
| Date Deposited: |
10 Nov 2011 19:50 |
| Last Modified: |
15 Nov 2016 13:45 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/8327 |
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