The C-terminal activating region 2 of the Epstein-Barr virus-encoded latent membrane protein 1 activates NF-κB through TRAF6 and TAK1

Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is oncogenic and indispensable for EBV-mediated B cell transformation. LMP1 is capable of activating several intracellular signaling pathways including the NF-kappa B pathway, which contributes to the EBV-mediated cell transformation. Two regions in the cytoplasmic carboxyl tail of LMP1, namely C-terminal activating regions 1 and 2 (CTAR1 and CTAR2), are responsible for NF-kappa B activation, with CTAR2 being the main NF-kappa B activator. Although the CTAR1-mediated NF-kappa B activation was previously shown to be TRAF3-dependent, we showed here that the CTAR2-mediated NF-kappa B activation is mainly TRAF6-dependent but TRAF2/5-independent. In contrast to the interleukin-1 receptor/toll-like receptor-mediated NF-kappa B pathways, the CTAR2-mediated NF-kappa B pathway does not require MyD88, IRAK1, or IRAK4 for TRAF6 engagement. Furthermore, we showed that TAK1 is required for NF-kappa B activation by LMP1. Thus, LMP1 utilizes two distinct pathways to activate NF-kappa B: a major one through CTAR2/TRAF6/TAK1/IKK beta (canonical pathway) and a minor one through CTAR1/TRAF3/NIK/IKK alpha (noncanonical pathway).