Epstein-Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-kappaB2 to p52 via an IKKgamma/NEMO-independent signalling pathway.
The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) constitutively activates the 'canonical' NF-kappaB pathway that involves the phosphorylation and degradation of IkappaBalpha downstream of the IkappaB kinases (IKKs). In this study, we show that LMP1 also promotes the proteasome-mediated proteolysis of p100 NF-kappaB2 resulting in the generation of active p52, which translocates to the nucleus in complex with the p65 and RelB NF-kappaB subunits. LMP1-induced NF-kappaB transactivation is reduced in nf-kb2(-/-) mouse embryo fibroblasts, suggesting that p100 processing contributes to LMP1-mediated NF-kappaB 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-kappaB pathway is impaired in cells lacking IKKgamma/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 IKKgamma. These data point to the existence of a novel signalling pathway that regulates NF-kappaB in LMP1-expressing cells, and may thereby play a role in both oncogenic transformation and the establishment of persistent EBV infection.
Cancer Research UK Institute for Cancer Studies, The University of Birmingham Medical School, Birmingham B15 2TA, UK. A.G.Eliopoulos@bham.ac.uk
Aristides G
AG
Eliopoulos
Jorge H
JH
Caamano
Joanne
J
Flavell
Gary M
GM
Reynolds
Paul G
PG
Murray
Jean-Luc
JL
Poyet
Lawrence S
LS
Young
D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D051550:I-kappa B Kinase; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA; D015533:Transcriptional Activation; D014162:Transfection; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D051996:Transcription Factor RelA; D014763:Viral Matrix Proteins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse