Submitted March 16, 2007
Accepted January 19, 2008
EBV LMP2A affects LMP1-mediated NF-
B signaling and survival of lymphoma cells by regulating TRAF2 expression
Ilaria Guasparri, Darya Bubman, and Ethel Cesarman*
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, United States
* Corresponding author; email: ecesarm{at}med.cornell.edu.
A mechanism used by Epstein-Barr virus (EBV) for in vitro transformation of B cells into lymphoblastoid cell lines (LCLs) is activation of the NF-
B pathway, which is largely mediated by the EBV latent membrane protein 1 (LMP1). LMP1 is coexpressed with LMP2A in many EBV-associated lymphoid malignancies. Since inhibition of NF-B leads to apoptosis of EBV-infected LCL and lymphoma cell lines, we sought to determine whether LMP1 alone, or in combination with other viral proteins, is responsible for initiating NF-B activation in these cells, thereby playing a role in cell survival. We found that suppression of LMP1 by RNA interference results in inhibition of basal NF-B and induction of apoptosis. Unexpectedly, knockdown of LMP2A also resulted in comparable decrease of NF-B activity and apoptosis. We report that LMP2A protein controls the expression of TRAF2 mRNA, which in turn is necessary for signaling by LMP1. Our data contrasts with previous studies showing that transfected LMP1 can signal in the absence of LMP2A or TRAF2, and demonstrate that both LMP2A and TRAF2 are required for survival in naturally infected lymphoma cells and LCLs. These results also support LMP1, LMP2A and TRAF2 as potential therapeutic targets in a subset of EBV-associated lymphoid malignancies.
