The cytoplasmic C-terminus of Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1) is essential for B lymphocyte growth transformation and is now shown to interact with a novel human protein (LMP1-associated protein 1 [LAP1]). LAN is homologous to a murine protein, tumor necrosis factor receptor-associated factor 2 (TRAF2), implicated in growth signaling from the p80 TNFR. A second novel protein (EBI6), induced by EBV infection, is the human homolog of a second murine TNFR-associated protein (TRAF1). LMP1 expression causes LAPP and EBI6 to localize to LMP1 clusters in lymphoblast plasma membranes, and LMPI coimmunoprecipitates with these proteins. LAPI binds to the p80 TNFR, CD40, and the lymphotoxin-β receptor, while EBI6 associates with the p80 TNFR. The interaction of LMP1 with these TNFR family-associated proteins is further evidence for their role in signaling and links LMP1-mediated transformation to signal transduction from the TNFR family.
Bibliographical noteFunding Information:
The corresponding author for this work is E. K. We are grateful to S. Elledge for the GAL4-transactivating domain cDNA library and for reagents necessary for the two-hybrid screening and to J. Reed for GST constructs. We thank K. Kaye, E. Hatzivassiliou, E. Robertson, K. Izumi, J. Minton, D. Tzamarias, W. Lesslauer, S. Fields, and J. Pietenpol for reagents and helpful discussions. L. Vara provided excellent technical assistance. This work was supported by grant CA47006 from the National Cancer Institute (to E. K.), grant IM663 from the American Cancer Society (to C. W.), and grant RT0261 from the Cigarette and Tobacco Surtax Fund of the State of California through the Tobacco-Related Diseases Research Program (to C. W). G. M. was supported by a postdoctoral fellowship of the Leukemia Society of America, and M. B. was supported by a Physician Scientist Award (grant 5K11CA01341) of the National Cancer Institute of the United States Public Health Service, by a Scholarship of the James S. McDon-nell Foundation, and by a Junior Faculty Research Award of the American Cancer Society. R. Y. was supported by a National Research Service Award of the U. S. Public Health Service (AI08548-02).