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The effect of Adenovirus E1A on the human immunoproteasome and MHC complex

Berhane, Sarah (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

Adenovirus E1A (AdE1A) is a viral oncoprotein that targets many cellular proteins and pathways, mainly those involved in transcriptional regulation. Proteasomes represent the major non-lysosomal mechanism responsible for protein degradation. Following interferon-γ treatment, three proteasome subunits are replaced by immunosubunits LMP2, LMP7 and MECL-1 producing immunoproteasomes. The proteasome and immunoproteasome generate peptide antigens for MHC class I presentation to cytotoxic T-cells. In this study, the effect of AdE1A on human immunoproteasomes as well as MHC class I and class II cell surface expression was examined.

It was found that AdE1A interacts with the immunoproteasome subunit MECL-1 through its N-terminal and CR3 regions. AdE1A also down-regulated all three immunosubunit expressions during adenovirus infection, transformation and AdE1A transfection, with the exception of Ad5-transformed cells where immunosubunit expression remained unchanged. Furthermore, MHC class I expression remained unaffected in the same three backgrounds. However, in the Ad12 transformants MHC class I was generally reduced prior to IFNγ treatment but was expressed after. MHC class II surface expression, in contrast, was down-regulated in all cases, except in Ad5 infected cells. Similarly, AdE1A reduced IFNγ-stimulated STAT1 phosphorylation and transcriptional response to IFNγ. And finally, T-cell recognition of target cells was reduced in the presence of AdE1A.

In conclusion, AdE1A targets the human immunoproteasome, both through direct binding and down-regulation of expression. It also targets the expression of MHC class I and class II surface expression.

Type of Work:Ph.D. thesis.
Supervisor(s):Grand, Roger and Steele, Jane
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Cancer Studies
Subjects:RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:3369
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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