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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:551393 |
| Date | January 2012 |
| Creators | Berhane, Sarah |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/3369/ |
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