TAK1 is a component of the Epstein-Barr virus LMP1 complex and is essential for activation of JNK but not of NF-κB

Epstein-Barr virus latent membrane protein 1 (LMP1) activates NF-kappa B and c-Jun N-terminal kinase (JNK), which is essential for LMP1 oncogenic activity. Genetic analysis has revealed that tumor necrosis factor receptor-associated factor 6 (TRAF6) is an indispensable intermediate of LMP1 signaling leading to activation of both NF-kappa B and JNK. However, the mechanism by which LMP1 engages TRAF6 for activation of NF-kappa B and JNK is not well understood. Here we demonstrate that TAK1 mitogen-activated protein kinase kinase kinase and TAK1-binding protein 2 (TAB2), together with TRAF6, are recruited to LMP1 through its N-terminal transmembrane region. The C-terminalcytoplasmicregionofLMP1facilitatestheassemblyofthiscomplex and enhances activation of JNK. In contrast, I kappa B kinase gamma is recruited through the C-terminal cytoplasmic region and this is essential for activation of NF-kappa B. Furthermore, we found that ablation of TAK1 resulted in the loss of LMP1-induced activation of JNK but not of NF-kappa B. These results suggest that an LMP1-associated complex containing TRAF6, TAB2, and TAK1 plays an essential role in the activation of JNK. However, TAK1 is not an exclusive intermediate for NF-kappa B activation in LMP1 signaling.