The C-terminal Activating Region 2 of the Epstein-Barr Virus-encoded Latent Membrane Protein 1 Activates NF-κB through TRAF6 and TAK1

Abstract 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-κB 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-κB activation, with CTAR2 being the main NF-κB activator. Although the CTAR1-mediated NF-κB activation was previously shown to be TRAF3-dependent, we showed here that the CTAR2-mediated NF-κB activation is mainly TRAF6-dependent but TRAF2/5-independent. In contrast to the interleukin-1 receptor/toll-like receptor-mediated NF-κB pathways, the CTAR2-mediated NF-κB pathway does not require MyD88, IRAK1, or IRAK4 for TRAF6 engagement. Furthermore, we showed that TAK1 is required for NF-κB activation by LMP1. Thus, LMP1 utilizes two distinct pathways to activate NF-κB: a major one through CTAR2/TRAF6/TAK1/IKKβ (canonical pathway) and a minor one through CTAR1/TRAF3/NIK/IKKα (noncanonical pathway).