Eliopoulos, Aristides G, Caamano, Jorge H, Flavell, Joanne, Reynolds, Gary M, Murray, Paul G, Poyet, Jean-Luc, and Young, Lawrence S
The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) constitutively activates the ‘canonical’ NF-?B pathway that involves the phosphorylation and degradation of I?Ba downstream of the I?B kinases (IKKs). In this study, we show that LMP1 also promotes the proteasome-mediated proteolysis of p100 NF-?B2 resulting in the generation of active p52, which translocates to the nucleus in complex with the p65 and RelB NF-?B subunits. LMP1-induced NF-?B transactivation is reduced in nf-kb2-/- mouse embryo fibroblasts, suggesting that p100 processing contributes to LMP1-mediated NF-?B 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-?B pathway is impaired in cells lacking IKK?/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 IKK?. These data point to the existence of a novel signalling pathway that regulates NF-?B in LMP1-expressing cells, and may thereby play a role in both oncogenic transformation and the establishment of persistent EBV infection.Oncogene (2003) 22, 7557-7569. doi:10.1038/sj.onc.1207120 [ABSTRACT FROM AUTHOR]