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PMID: 9733827 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Role of the TRAF binding site and NF-kappaB activation in Epstein-Barr virus latent membrane protein 1-induced cell gene expression.

Journal of virology ·Vol. 72 ·No. 10 ·1998-10-00 ·Pages 7900-8

Devergne O, Cahir McFarland ED, Mosialos G, Izumi KM, Ware CF, Kieff E

Abstract

In this study, we investigated the induction of cellular gene expression by the Epstein-Barr Virus (EBV) latent membrane protein 1 (LMP1). Previously, LMP1 was shown to induce the expression of ICAM-1, LFA-3, CD40, and EBI3 in EBV-negative Burkitt lymphoma (BL) cells and of the epidermal growth factor receptor (EGF-R) in epithelial cells. We now show that LMP1 expression also increased Fas and tumor necrosis factor receptor-associated factor 1 (TRAF1) in BL cells. LMP1 mediates NF-kappaB activation via two independent domains located in its C-terminal cytoplasmic tail, a TRAF-interacting site that associates with TRAF1, -2, -3, and -5 through a PXQXT/S core motif and a TRADD-interacting site. In EBV-transformed B cells or transiently transfected BL cells, significant amounts of TRAF1, -2, -3, and -5 are associated with LMP1. In epithelial cells, very little TRAF1 is expressed, and only TRAF2, -3, and -5, are significantly complexed with LMP1. The importance of TRAF binding to the PXQXT/S motif in LMP1-mediated gene induction was studied by using an LMP1 mutant that contains alanine point mutations in this motif and fails to associate with TRAFs. This mutant, LMP1(P204A/Q206A), induced 60% of wild-type LMP1 NF-kappaB activation and had approximately 60% of wild-type LMP1 effect on Fas, ICAM-1, CD40, and LFA-3 induction. In contrast, LMP1(P204A/Q206A) was substantially more impaired in TRAF1, EBI3, and EGF-R induction. Thus, TRAF binding to the PXQXT/S motif has a nonessential role in up-regulating Fas, ICAM-1, CD40, and LFA-3 expression and a critical role in up-regulating TRAF1, EBI3, and EGF-R expression. Further, D1 LMP1, an LMP1 mutant that does not aggregate failed to induce TRAF1, EBI3, Fas, ICAM-1, CD40, and LFA-3 expression confirming the essential role for aggregation in LMP1 signaling. Overexpression of a dominant form of IkappaBalpha blocked LMP1-mediated TRAF1, EBI3, Fas, ICAM-1, CD40, and LFA-3 up-regulation, indicating that NF-kappaB is an important component of LMP1-mediated gene induction from both the TRAF- and TRADD-interacting sites.

MeSH Terms
Binding Sites Cell Line, Transformed ErbB Receptors/genetics Gene Expression Regulation, Viral Herpesvirus 4, Human/metabolism Humans Intercellular Adhesion Molecule-1/genetics NF-kappa B/metabolism Protein Binding Receptors, Tumor Necrosis Factor/metabolism Transcriptional Activation Up-Regulation Viral Matrix Proteins/metabolism
Chemicals
EBV-associated membrane antigen, Epstein-Barr virus NF-kappa B Receptors, Tumor Necrosis Factor Viral Matrix Proteins Intercellular Adhesion Molecule-1 ErbB Receptors
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Devergne O
INSERM U131 and Institut Paris-Sud sur les Cytokines, 92140 Clamart, France.
Cahir McFarland E D
Mosialos G
Izumi K M
Ware C F
Kieff E
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.72.10.7900-7908.1998
Published
1998-10-00
Pages
7900-8
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC110117
Subset
IM
Grants
NIAID NIH HHS · T32 AI007061 · United States
NIAID NIH HHS · AI 07061-20 · United States
NCI NIH HHS · R01 CA047006 · United States
NCI NIH HHS · R35 CA047006 · United States
NCI NIH HHS · CA470006 · United States
External Links
PubMed source DOI: 10.1128/JVI.72.10.7900-7908.1998 PMC Full Text View journal details
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