Elucidation of the NF-kB pathway mediated by Epstein - Barr virus-encoded latent membrane protein 1 (LMP1)

Epstein - Barr virus (EBV) is a γ-herpes virus containing double-stranded DNA. A unique feature of EBV lies in its ability in transforming B cell. EBV infection is quite common in world human population and has been casually linked to several human malignancies, including Burkitt's lymphoma, Hodgkins's disease, lymphoproliferative disorders, and nasopharyngeal carcinoma (NPC). 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 the C-terminal activating region 1 and 2 (CTAR1 and CTAR2), are responsible for NF-κB activation, with CTAR2 being the main NF-κB activator. While 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 does not require MyD88, IRAK1 or IRAK4 for TRAF6 engagement. Furthermore, we showed that TAK1 is required for NF-κB activation by LMP1. Taken together, these results demonstrated that LMP1 activates the major canonical NF-κB pathway through CTAR2/TRAF6/TAK1/IKKβ. In addition to activation of the canonical NF-κB pathway, previous studies by other groups showed that LMP1 also activates the minor non-canonical NF-κB pathway through CTAR1/TRAF3/NIK/IKKα. In our current study, we first confirmed the ability of LMP1 in inducing non-canonical NF-κB activation. To our surprise, we found that both CTAR1 and CTAR2 are involved in LMP1-mediated non-canonical NF-κB activation. Furthermore, our result showed that the lack of either TRAF2/5, TRAF3 or TRAF6 in cells could not completely abolish LMP1- mediated non-canonical NF-κB activation, suggesting a redundant role for TRAF2/5, TRAF3 and TRAF6 in this process. Further investigation of the mechanism underlying the LMP1-mediated non-canonical NF-κB pathway is currently underway