Erazo, Angela
(2010)
VARICELLA-ZOSTER VIRUS ORF66 KINASE:REVEALING CRITICAL CELL-SPECIFIC ROLES OF THE KINASE AND ITS TARGETING OF THE NUCLEAR MATRIX PROTEIN, MATRIN 3.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Varicella-Zoster Virus (VZV) is the causative agent of chickenpox during primary infection and herpes-zoster or shingles following reactivation from neuronal latency. The VZV ORF66 protein kinase is a serine/threonine kinase and one of two VZV protein kinases. Its homologue in the alphaherpesviruses are termed the US3 kinases, and through phosphorylation of targets affect many events in infection, influencing processes such as survival of the infected cell to apoptosis, the state of permissivity to gene expression, avoidance of immunity, modulating cellular pathways affecting host actin dynamics, and influencing the nuclear structure and nuclear membrane to enable assembly of virus components. ORF66 is not essential in most cell culture but important for viral replication in T cells. In this work, we have found the ORF66 is critical for viral growth in primary corneal fibroblasts and thus established a model for further investigatation of cell-type dependent functions for ORF66. This finding may have important applications for viral pathogenesis as VZV reactivates and causes infection of the eye in herpes zoster ophthalmicus disease. Here we also describe a novel ORF66 cellular target, the nuclear matrix protein, matrin 3. Specific matrin 3 phosphorylation is conserved for herpes simplex virus - type 1 and pseudorabies virus US3 kinases. Thus, this finding may have important implications for the role of ORF66/US3 function in common alphaherpesvirus strategies to utilize host cell machinery in establishing a host cell environment conducive to viral replication. ORF66/US3-induced phosphorylation of matrin 3 was needed for matrin nuclear retainment late in viral infection, suggesting that ORF66/US3 may have a role in modulating matrin 3 nuclear functions needed for viral replication. The ORF66 kinase is clearly important for VZV growth in certain cell types relevant to human disease and our studies underscore the diverse roles of this protein in VZV infection.
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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Unpublished |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: |
14 July 2010 |
| Date Type: |
Completion |
| Defense Date: |
26 May 2010 |
| Approval Date: |
14 July 2010 |
| Submission Date: |
13 March 2010 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Virology and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
cornea stromal fibroblasts; viral kinases; alphaherpesvirus; PKA substrate; US3 kinase; virus host interactions |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-03132010-121507/, etd-03132010-121507 |
| Date Deposited: |
10 Nov 2011 19:32 |
| Last Modified: |
19 Dec 2016 14:35 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/6493 |
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