The Journal of Experimental Medicine
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Published online 23 February 2004 doi:10.1084/jem.20031255
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 5, 661-671
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Requirement for TRAF3 in Signaling by LMP1 But Not CD40 in B Lymphocytes

Ping Xie1, Bruce S. Hostager3, and Gail A. Bishop1,2,4

1 Department of Microbiology, 2 Department of Internal Medicine, and 3 Department of Pediatrics, The University of Iowa
4 Veterans Affairs Medical Center, Iowa City, IA 52242

Address correspondence to Gail A. Bishop, Dept. of Microbiology, University of Iowa, 3-570 Bowen Science Bldg., Iowa City, IA 52242. Phone: (319) 335-7945; Fax: (319) 335-9006; email: gail-bishop{at}uiowa.edu

CD40, a member of the tumor necrosis factor receptor family, and the Epstein-Barr virus–encoded oncoprotein latent membrane protein 1 (LMP1) share several tumor necrosis factor receptor–associated factor (TRAF) adaptor proteins for signaling. Among these, TRAF3 was the first identified to directly bind both receptors, yet its role remains a mystery. To address this, we generated B cell lines deficient in TRAF3 by homologous recombination. We found that CD40 signals were normal in the absence of TRAF3, with the exception of moderately enhanced c-Jun NH2-terminal kinase (JNK) activation and antibody secretion. In sharp contrast, LMP1 signaling was markedly defective in TRAF3-/- B cells. LMP1-induced activation of JNK and nuclear factor {kappa}B, up-regulation of CD23 and CD80, and antibody secretion were substantially affected by TRAF3 deficiency. Reconstitution of TRAF3 expression decreased CD40-induced JNK activation and antibody secretion, and fully restored LMP1 signaling. Although TRAF2 is widely believed to be important for LMP1 function, LMP1 signaling was intact in TRAF2-/- B cells. Our data reveal that CD40 and LMP1 unexpectedly use TRAF3 in different ways, and that TRAF3 is required for LMP1-mediated activation of B cells.

Key Words: TNF-R family • Epstein-Barr virus • antibody secretion • signal transduction • B cell

The online version of this article includes supplemental material.

Abbreviations used in this paper: CCT, cytoplasmic carboxyl terminus; DN, dominant-negative; hCD40, human CD40; IPTG, isopropyl-ß-D-thiogalactopyranoside; JNK, c-Jun NH2-terminal kinase; LMP1, latent membrane protein 1; mCD40, mouse CD40; NF-{kappa}B, nuclear factor {kappa}B; Pfc, plaque-forming cell; Sf9, Spodoptera frugiperda; TRAF, TNF-R–associated factor.


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