The Journal of Experimental Medicine
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Published online 16 April 2001.
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© The Rockefeller University Press, 0022-1007/2001/4/943/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 8, April 16, 2001 943-954

Original Article

Differential Signaling and Tumor Necrosis Factor Receptor–Associated Factor (Traf) Degradation Mediated by Cd40 and the Epstein-Barr Virus Oncoprotein Latent Membrane Protein 1 (Lmp1)

Kevin D. Browna,b, Bruce S. Hostagerc, and Gail A. Bishopb,c,d,e

a Medical Scientist Training Program, University of Iowa,
b Immunology Graduate Program, University of Iowa,
c Department of Microbiology, University of Iowa,
d Department of Internal Medicine, University of Iowa,
e Veteran's Affairs Medical Center, Iowa City, Iowa 52242
3-570 Bowen Science Bldg., Dept. of Microbiology, University of Iowa, Iowa City, IA 52242.319-335-9006319-335-7945

gail-bishop{at}uiowa.edu

Latent membrane protein 1 (LMP1) plays a critical role in B cell transformation by Epstein-Barr virus (EBV) and appears to mimic a constitutively active CD40 receptor. Intracellular tumor necrosis factor (TNF) receptor–associated factor (TRAF) adapter proteins, shown to contribute to signaling by both CD40 and LMP1, were recruited by both molecules to lipid-enriched membrane rafts. However, we found that TRAFs 2 and 3 were subsequently degraded after CD40- but not LMP1-induced signaling. This degradation was proteasome-dependent and required direct TRAF binding by CD40. Using a model system designed to directly compare the signaling potency of the cytoplasmic domains of LMP1 and CD40 in B lymphocytes, we found that LMP1 more potently activates c-Jun kinase and nuclear factor {kappa}B and induces higher levels of several B cell effector functions than does CD40. This suggests that LMP1 utilizes a modified CD40 signaling pathway. Failure to regulate TRAFs may contribute to the enhanced capacity of LMP1 to activate B cells as well as promote B cell transformation.

Key Words: HHV4 • CD40 • signal transduction • B lymphocyte • lymphoma

Abbreviations used in this paper: CHO, Chinese hamster ovary; EMSA, electrophoretic mobility shift assay; HRP, horseradish peroxidase; ICAM; intercellular adhesion molecule; JNK, c-Jun kinase; LFA, lymphocyte function–associated antigen; LMP, latent membrane protein; MCF, mean channel fluorescence; NF, nuclear factor; TRAF, TNF receptor–associated factor; WT, wild-type.

© 2001 The Rockefeller University Press


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