TY - JOUR
T1 - The Epstein-Barr virus encoded latent infection membrane protein 1 (LMP1) regulates the processing of p100 NK-κB2 to p52 via an IKKγ/NEMO-independent signaling pathway
AU - Eliopoulos, Aristides
AU - Caamano, Jorge
AU - Gough, Joanne
AU - Reynolds, Gary
AU - Murray, Paul
AU - Poyet, JL
AU - Young, Lawrence
PY - 2003/10/23
Y1 - 2003/10/23
N2 - 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-expressingcells, and may thereby play a role in both oncogenic transformation and the establishment of persistent EBV infection.
AB - 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-expressingcells, and may thereby play a role in both oncogenic transformation and the establishment of persistent EBV infection.
KW - LMP1
KW - NF-kappa B2
KW - EBV
KW - signalling
UR - http://www.scopus.com/inward/record.url?scp=0344441264&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1207120
DO - 10.1038/sj.onc.1207120
M3 - Article
C2 - 14576817
SN - 0950-9232
VL - 22
SP - 7557
EP - 7569
JO - Oncogene
JF - Oncogene
IS - 48
ER -