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Functional Analysis and Characterization of Epstein Barr Virus Latent Membrane Protein 2b

Tomaszewski-Flick, Monica Jo (2008) Functional Analysis and Characterization of Epstein Barr Virus Latent Membrane Protein 2b. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Epstein Barr virus persists in the human host by establishing a latent infection following primary infection. The virus periodically reactivates; producing virus that can infect new cells or be shed in saliva to infect new hosts. EBV is also implicated in malignant B cell proliferation in the immunocompromised and a variety of haemopoetic cancers, indicating that it is of public health significance.The LMP2 gene of EBV encodes 2 protein isoforms: a 497aa protein (LMP2a) and a 378aa protein (LMP2b). These isoforms are identical, with the exception of an N-terminal cytoplasmic signaling domain of 119aa encoded in the LMP2a exon 1. The remaining residues (including the entirety of LMP2b) encode an integral membrane protein consisting of 12 transmembrane spanning regions with short alternating intracellular and extracellular connection loops.Most research on the LMP2 isoforms has focused on the LMP2a protein and it's role in blocking B-cell receptor mediated signaling, degradation of associated proteins, and transformation. LMP2b, lacking the obvious signaling domain, has been largely ignored. Recently studies have suggested that LMP2b is a negative regulator of LMP2a.In the following studies, we have evaluated the contribution of LMP2b to the block in BCR signaling using LMP2b expressing BJAB cell line. Our results demonstrate that LMP2b has the ability to singularly block BCR signaling.LMP2 proteins have been described at both the plasma membrane as well as in the intracellular membranes of cells. Our studies indicate that the intact 12-TM region of the LMP2 proteins is necessary for intracellular localization. Through progressive deletions of 2TM segments from both the N- and C-terminal ends of the protein, we find that an intact 12-TM domain is necessary for localization, and there are at least 2 domains required for multimerization.The role of LMP2 in immortalization is also contested, with groups reporting that LMP2a is both necessary and dispensable for immortalization. We utilized an established system of recombinant EBV construction to demonstrate that LMP2a, but not LMP2b plays a role in establishment and maintenance of viral latency.Taken together, these results indicate a function for LMP2b in signaling and immortalization separate from LMP2a.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tomaszewski-Flick, Monica Jomonicajo@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRowe, David T.rowe1@pitt.eduROWE1
Committee MemberKinchington, Paulkinchingtonp@upmc.eduKINCH
Committee MemberWatkins, Simonswatkins@pitt.eduSWATKINS
Committee MemberAyyavoo, Velpandivelpandi@pitt.eduVELPANDI
Date: 28 September 2008
Date Type: Completion
Defense Date: 12 May 2008
Approval Date: 28 September 2008
Submission Date: 5 June 2008
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: BAC; EBV; Herpesviruses; B-cell signalling; HHV-4
Other ID: http://etd.library.pitt.edu/ETD/available/etd-06052008-104418/, etd-06052008-104418
Date Deposited: 10 Nov 2011 19:46
Last Modified: 19 Dec 2016 14:36
URI: http://d-scholarship.pitt.edu/id/eprint/8015

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