Epstein–Barr virus-encoded LMP-1 and CD40 mediate IL-6 production in epithelial cell via an NF-kB pathway involving TNF receptor-associated factors

Harvard University, Cambridge, Massachusetts, United States
Oncogene (Impact Factor: 8.56). 07/1997; 14(24):2899-916. DOI: 10.1038/sj.onc.1201258
Source: PubMed

ABSTRACT Expression of the Epstein-Barr virus (EBV) transforming LMP1 in B cells activates the transcription factor NF-kappaB and induces phenotypic changes through two distinct domains in the cytoplasmic C-terminus of the protein. The aa 187-231 domain of LMP1, which is important for growth transformation, binds tumour necrosis factor (TNF) receptor associated factor (TRAF) 1 and TRAF3 and this interaction mediates subsequent signalling events. The TRAFs also associate with CD40, a member of the TNFR family, which upon ligation activates NF-kappaB and induces phenotypic changes similar to those mediated by LMP1. This study demonstrates that LMP1 expression in carcinoma cell lines and SV40-transformed keratinocytes results in induction of the pleiotropic cytokine interleukin 6 (IL6), an effect which is also observed upon CD40 ligation. The mechanism by which either LMP1 expression or CD40 ligation induces IL6 production was found to be NF-kappaB-dependent. Mutational analysis identified domains in the C-terminus of LMP1 which are important for NF-kappaB activation and IL6 secretion. LMP1 and CD40 share a common PxQxT core TRAF binding motif and mutations in or adjacent to this sequence impaired the ability of LMP1 or CD40 to induce NF-kappaB activation and IL6 secretion. The importance of TRAF interactions in mediating these effects was confirmed using dominant negative TRAF2 and TRAF3 mutants which also identified differences in the signalling events mediated by the two NF-kappaB activating domains of LMP1. A20, an anti-apoptotic protein which interacts with TRAF2 and blocks CD40-mediated NF-kappaB activity, also blocked NF-kappaB and IL6 secretion in LMP1-transfected epithelial cells. These results suggest that LMP1 regulates IL6 production in epithelial cells in a manner similar to CD40 ligation and implicate TRAFs as common mediators in the transduction of signals generated via the CD40 and LMP1 pathways. As a role for IL6 in regulating epithelial cell growth has previously been suggested, the control of IL6 secretion via the CD40 and LMP1 pathways may have implications for the growth of both normal and transformed epithelial cells.

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Available from: Lawrence S Young, Jun 11, 2014
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    • "EBNA-1 can also be classifi ed into fi ve subtypes: P-ala, P-thr, V-val, V-leu, and V-pro based on the polymorphism of amino acids at position 487 (Bhatia et al. 1996; Gutierrez et al. 1997; Snudden et al. 1995), which has been associated with geographical location or disease status (Imai et al. 1998; Zhang et al. 2004). LMP1 is an EBV oncogene expressed frequently in EBV-associated malignancies (Eliopoulos et al. 1997; Kilger et al. 1998; Wang et al. 1985 "
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    • "LMP1 activates MAPK pathways. LMP1 can activate the transcription factor AP-1 via mitogen-activated protein kinases (MAPKs) c-jun N-terminal kinase 1 (JNK1) and p38 in B cells and epithelial cells (Eliopoulos & Young, 1998; Eliopoulos et al., 1999a, b; Kieser et al., 1997). In 293 epithelial cells, JNK activation was dependent on aa 379–384, overlapping the CTAR-2 domain and TRADDbinding domain, but not on CTAR-1 (Kieser et al., 1997, 1999; Eliopoulos & Young, 1998; Eliopoulos et al., 1999b). "
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