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.

Abstract

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.

• Authors: Aristides G Eliopoulos, Jorge H Caamano, Joanne Flavell, Gary M Reynolds, Paul G Murray, Jean-Luc Poyet, Lawrence S Young
• Journal: Oncogene (Oncogene) Vol. 22 Issue 48 Pg. 7557-69 (Oct 23 2003) ISSN: 0950-9232 [Print] England
• PMID: 14576817 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• EBV-associated membrane antigen, Epstein-Barr virus
• NF-kappa B
• NF-kappa B p52 Subunit
• Transcription Factor RelA
• Viral Matrix Proteins
• Protein Serine-Threonine Kinases
• CHUK protein, human
• Chuk protein, mouse
• I-kappa B Kinase
• IKBKB protein, human
• IKBKE protein, human
• Ikbkb protein, mouse
• Ikbke protein, mouse

Topics

• Active Transport, Cell Nucleus
• Animals
• Cell Line, Tumor
• Electrophoretic Mobility Shift Assay
• Humans
• I-kappa B Kinase
• Mice
• NF-kappa B (metabolism)
• NF-kappa B p52 Subunit
• Protein Processing, Post-Translational
• Protein Serine-Threonine Kinases (metabolism)
• Signal Transduction
• Transcription Factor RelA
• Transcriptional Activation
• Transfection
• Viral Matrix Proteins (genetics, metabolism)