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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-03132010-121507 |
| Date | 14 July 2010 |
| Creators | Erazo, Angela |
| Contributors | Thomas E. Smithgall, Frederick L. Homa, Donald B. DeFranco, Ora A. Weisz, Paul R. Kinchington |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-03132010-121507/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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