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Epstein–Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-κB2 to p52 via an IKKγ/NEMO-independent signalling pathway

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Abstract

The oncogenic Epstein–Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) constitutively activates the ‘canonical’ NF-κB pathway that involves the phosphorylation and degradation of IκBα downstream of the IκB kinases (IKKs). In this study, we show that LMP1 also promotes the proteasome-mediated proteolysis of p100 NF-κB2 resulting in the generation of active p52, which translocates to the nucleus in complex with the p65 and RelB NF-κB subunits. LMP1-induced NF-κB transactivation is reduced in nf-kb2−/− mouse embryo fibroblasts, suggesting that p100 processing contributes to LMP1-mediated NF-κB transcriptional effects. This pathway is likely to operate in vivo, as the expression of LMP1 in primary EBV-positive Hodgkin's lymphoma and nasopharyngeal carcinoma biopsies correlates with the nuclear accumulation of p52. Interestingly, while the ability of LMP1 to activate the canonical NF-κB pathway is impaired in cells lacking IKKγ/NEMO, the regulatory subunit of the IKK complex, p100 processing remains unaffected. As a result, nuclear translocation of p52, but not p65, occurs in the absence of IKKγ. These data point to the existence of a novel signalling pathway that regulates NF-κB in LMP1-expressing cells, and may thereby play a role in both oncogenic transformation and the establishment of persistent EBV infection.

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Acknowledgements

We are grateful to C Dawson, H Huang, J Inoue, E Kieff, L Laverick, N Perkins, M Rowe, K Ryan, G Tsao, S Yamaoka and D Wallach for providing us with reagents, and to Liz Hodgkins for technical assistance. This work was supported by a Medical Research Council (MRC, UK) Career Development Award to AGE and by a Cancer Research UK Grant (SP2584) to AGE and LSY.

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Authors and Affiliations

  1. Cancer Research UK Institute for Cancer Studies, The University of Birmingham Medical School, Birmingham, B15 2TA, UK

    Aristides G Eliopoulos, Joanne Flavell, Gary M Reynolds, Paul G Murray & Lawrence S Young

  2. MRC Centre for Immune Regulation, The University of Birmingham Medical School, Birmingham, B15 2TA, UK

    Aristides G Eliopoulos, Jorge H Caamano & Lawrence S Young

  3. Department of Pathology, The University of Birmingham Medical School, Birmingham, B15 2TA, UK

    Joanne Flavell, Gary M Reynolds & Paul G Murray

  4. INSERM U532, Institut de Recherche sur la Peau, Hopital Saint-Louis, Paris, Cedex 10, 75475, France

    Jean-Luc Poyet

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  1. Aristides G Eliopoulos
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Correspondence to Aristides G Eliopoulos.

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Eliopoulos, A., Caamano, J., Flavell, J. et al. Epstein–Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-κB2 to p52 via an IKKγ/NEMO-independent signalling pathway. Oncogene 22, 7557–7569 (2003). https://doi.org/10.1038/sj.onc.1207120

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