Elucidation of the c-Jun N-Terminal Kinase Pathway Mediated by Epstein-Barr Virus-Encoded Latent Membrane Protein 1

Abstract

Epstein-Barr virus (EBV) is associated with several human diseases including infectious mononucleosis and nasopharyngeal carcinoma. EBV-encoded latent membrane protein 1 (LMP1) is oncogenic and indispensable for cellular transformation caused by EBV. Expression of LMP1 in host cells constitutively activates both the c-Jun N-terminal kinase (JNK) and NF-κB pathways, which contributes to the oncogenic effect of LMP1. However, the underlying signaling mechanisms are not very well understood. Based mainly on overexpression studies with various dominant-negative constructs, LMP1 was generally thought to functionally mimic members of the tumor necrosis factor (TNF) receptor superfamily in signaling. In contrast to the prevailing paradigm, using embryonic fibroblasts from different knockout mice and the small interfering RNA technique, we find that the LMP1-mediated JNK pathway is distinct from those mediated by either TNF-α or interleukin-1. Moreover, we have further elucidated the LMP1-mediated JNK pathway by demonstrating that LMP1 selectively utilizes TNF receptor-associated factor 6, TAK1/TAB1, and c-Jun N-terminal kinase kinases 1 and 2 to activate JNK.

We thank Tak Mak and A. Shahinian for TRAF6^−/− MEFs, G. Natoli for HA-TRAF6, Jerry Wang for critical reading of the manuscript, and Carol Wong for technical help.

This project was supported by a Central Allocation Grant from the Hong Kong Research Grant Council (CA01/02.SC02) and the Areas of Excellence Scheme (Project no. AoE/B-15/01).