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The EBV-encoded latent membrane proteins, LMP2A and LMP2B, limit the actions of interferon by targeting interferon receptors for degradation

Oncogene volume 28, pages 3903–3914 (2009)Cite this article

Abstract

Although frequently expressed in Epstein–Barr virus (EBV)-positive malignancies, the role that latent membrane protein 2A and 2B (LMP2A and LMP2B) have in the oncogenic process remains obscure. Here we show a novel function for these proteins in epithelial cells, namely, their ability to modulate signalling from type I/II interferon receptors (IFNRs). We show that LMP2A- and LMP2B-expressing epithelial cells show decreased responsiveness to interferon (IFN)α and IFNγ, as assessed by STAT1 phosphorylation, ISGF3 and GAF-mediated binding to IFN-stimulated response element and IFNγ-activated factor sequence elements and luciferase reporter activation. Transcriptional profiling highlighted the extent of this modulation, with both viral proteins impacting ‘globally’ on IFN-stimulated gene expression. Although not affecting the levels of cell-surface IFNRs, LMP2A and LMP2B accelerated the turnover of IFNRs through processes requiring endosome acidification. This function may form part of EBV's strategy to limit anti-viral responses and define a novel function for LMP2A and LMP2B in modulating signalling from receptors that participate in innate immune responses.

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Acknowledgements

This work was supported by programme funding from Cancer Research UK and the European Commission's FP6 Life Sciences Health Programme (INCA project LSHC-CT-.2005-018704).

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Author notes

  1. K M Shah and S E Stewart: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Research UK Institute for Cancer Studies, The Medical School, University of Birmingham, Birmingham, UK

    K M Shah, W Wei, C B J Woodman, J D O'Neil, C W Dawson & L S Young

  2. Division of Pathway Medicine, University of Edinburgh Medical School, Edinburgh, UK

    S E Stewart

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  1. K M Shah
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  2. S E Stewart
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  3. W Wei
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  7. L S Young
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Correspondence to L S Young.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Shah, K., Stewart, S., Wei, W. et al. The EBV-encoded latent membrane proteins, LMP2A and LMP2B, limit the actions of interferon by targeting interferon receptors for degradation. Oncogene 28, 3903–3914 (2009). https://doi.org/10.1038/onc.2009.249

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