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-kappaB 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-kappaB activation, with CTAR2 being the main NF-kappaB activator. Although the CTAR1-mediated NF-kappaB activation was previously shown to be TRAF3-dependent, we showed here that the CTAR2-mediated NF-kappaB activation is mainly TRAF6-dependent but TRAF2/5-independent. In contrast to the interleukin-1 receptor/toll-like receptor-mediated NF-kappaB pathways, the CTAR2-mediated NF-kappaB pathway does not require MyD88, IRAK1, or IRAK4 for TRAF6 engagement. Furthermore, we showed that TAK1 is required for NF-kappaB activation by LMP1. Thus, LMP1 utilizes two distinct pathways to activate NF-kappaB: a major one through CTAR2/TRAF6/TAK1/IKKbeta (canonical pathway) and a minor one through CTAR1/TRAF3/NIK/IKKalpha (noncanonical pathway).
Highlights
Various mammalian cell viruses exert their cytotoxic effects by interfering with the function of specific host factors and the cellular signaling pathways associated with these host factors, eventually leading to abnormal cellular processes
CTAR2 is solely responsible for the latent membrane protein 1 (LMP1)-induced JNK pathway, both CTAR1 and CTAR2 contribute to NF-B activation, with CTAR2 accounting for 70% of the total NF-B activity induced by LMP1 [8, 9]
When HEK293 cells were co-transfected with HA-IKK together with either form of LMP1, we showed that both forms of LMP1 significantly activated IKK to a similar extent (Fig. 1C), in agreement with the reporter assay above
Summary
Various mammalian cell viruses exert their cytotoxic effects by interfering with the function of specific host factors and the cellular signaling pathways associated with these host factors, eventually leading to abnormal cellular processes. Using immune complex kinase assays, we compared LMP1 with its mutant derivatives for their ability to activate the endogenous IKK after separately transfecting them into HEK293 cells. To find out which MAP3K acts in the LMP1-mediated NF-B pathway, we first co-transfected LMP1 and HA-IKK into MEFs derived from either the wild type or MEKK1 knock-out mice [41].
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