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

Abstract

The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) constitutively activates the 'canonical' NF-jB pathway that involves the phosphorylation and degradation of IjBa downstream of the IjB kinases (IKKs). In this study, we show that LMP1 also promotes the proteasome-mediated proteolysis of p100 NF-jB2 resulting in the generation of active p52, which translocates to the nucleus in complex with the p65 and RelB NF-jB subunits. LMP1-induced NF-jB transactivation is reduced in nf-kb2 À/À mouse embryo fibroblasts, suggesting that p100 processing contributes to LMP1-mediated NF-jB 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-jB pathway is impaired in cells lacking IKKc/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 IKKc. These data point to the existence of a novel signalling pathway that regulates NF-jB in LMP1-expressing cells, and may thereby play a role in both oncogenic transformation and the establishment of persistent EBV infection.

Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

“…In EBV, NF-kB is one of major signalling pathways induced by EBV LMP1 and essential for LMP1-induced transformation (Cahir McFarland et al, 1999;He et al, 2000). Importantly, LMP1 not only triggers canonical NF-kB (p65-p50) pathway but has also been demonstrated in the activation of the noncanonical NF-kB pathway, p100 NF-kB2 (Atkinson et al, 2003;Eliopoulos et al, 2003;Saito et al, 2003). In this study, comparison of the regions of LMP1 required for repression of p53-mediated DNA repair and transcription, and activation of NF-kB, revealed that they were located at either CTAR1 (a.a. 189-222) or CTAR2 (a.a. 350-386) of LMP1 and the transmembrane domain is required for these functions (Figure 6c-e).…”

LMP1 signaling and activation of NF-κB in LMP1 transgenic mice

“…In epithelial cells, LMP1 activates p50 homodimers, p50/p52, and p52/p65 heterodimers, as well as RelB (Paine et al, 1995;Miller et al, 1998;Eliopoulos et al, 2003a). In B-lymphocytes, LMP1 also activates RelB (Pai et al, 2002).…”

Aberrant NF-κB2/p52 expression in Hodgkin/Reed–Sternberg cells and CD30-transformed rat fibroblasts

“…These observations suggested an important role for NF-kB in the pathogenesis of HL. HL is often associated with Epstein-Barr virus (EBV), and several research groups including ours have recently demonstrated that the EBV-encoded latent membrane protein-1 activates the canonical and noncanonical NF-kB signaling pathways (Atkinson et al, 2003;Eliopoulos et al, 2003;Saito et al, 2003). Of note, constitutive IKK activation was observed both EBV-positive and -negative HL cell lines (Krappmann et al, 1999;Mathas et al, 2003).…”