The Journal of Experimental Medicine
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Published online 6 August 2001. doi:10.1084/jem.194.3.255
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© The Rockefeller University Press, 0022-1007/2001/8/255/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 3, August 6, 2001 255-264

Original Article

Epstein-Barr Virus Latent Membrane Protein 2a (Lmp2a) Employs the Slp-65 Signaling Module

Niklas Engelsa, Mark Merchantb, Rajita Pappuc, Andrew C. Chanc, Richard Longneckerb, and Jürgen Wienandsa

a Department of Biochemistry I, University of Bielefeld, Bielefeld D-33615, Germany
b Department of Microbiology and Immunology, Northwestern University Medical School, Chicago, IL 60611
c Center for Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110
Department of Biochemistry I, University of Bielefeld, Universitätsstrasse 25, Bielefeld D-33615, Germany.49-521-106-810549-521-106-2081

j.wienands{at}uni-bielefeld.de

In latently infected B lymphocytes, the Epstein-Barr virus (EBV) suppresses signal transduction from the antigen receptor through expression of the integral latent membrane protein 2A (LMP2A). At the same time, LMP2A triggers B cell survival by a yet uncharacterized maintenance signal that is normally provided by the antigen receptor. The molecular mechanisms are unknown as LMP2A-regulated signaling cascades have not been described so far. Using a novel mouse model we have identified the intracellular adaptor protein Src homology 2 (SH2) domain–containing leukocyte protein (SLP)-65 as a critical downstream effector of LMP2A in vivo. Biochemical analysis of the underlying signaling pathways revealed that EBV infection causes constitutive tyrosine phosphorylation of one of the two SLP-65 isoforms and complex formation between SLP-65 and the protooncoprotein CrkL (CT10 regulator of kinase like). This leads to antigen receptor-independent phosphorylation of Cbl (Casitas B lineage lymphoma) and C3G. In contrast, phospholipase C-{gamma}2 (PLC-{gamma}2) activation is completely blocked. Our data show that in order to establish a latent EBV infection, LMP2A selectively activates or represses SLP-65–regulated signaling pathways.

Key Words: B lymphocytes • Epstein-Barr virus • antigen receptor • SLP-65 • signal transduction

Abbreviations used in this paper: BCR, B cell antigen receptor; BLNK, B cell linker protein; Btk, Bruton's tyrosine kinase; Cbl, Casitas B lineage lymphoma; Crk, CT10 regulator of kinase; CrkL, Crk like; EBNA, EBV-associated nuclear antigen; GST, glutathione S-transferase; ITAM, immunoreceptor tyrosine-based activation motif; LCL, lymphoblastoid cell line; LMP2A, latent membrane protein 2A; PLC-{gamma}2, phospholipase C-{gamma}2; PTK, protein tyrosine kinase; pTyr, phosphotyrosine; RAG, recombination activating gene; SLP, SH2 domain-containing leukocyte protein; SH2, Src homology 2 domain; WT, wild-type.

© 2001 The Rockefeller University Press


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