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).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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B-Lymphocytes / metabolism
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Cell Line
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Cell Transformation, Neoplastic
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Genes, Reporter
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Humans
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I-kappa B Kinase / metabolism
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Interleukin-1 Receptor-Associated Kinases
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Intracellular Signaling Peptides and Proteins / metabolism
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Luciferases / metabolism
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MAP Kinase Kinase Kinases / metabolism*
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Myeloid Differentiation Factor 88
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NF-kappa B / metabolism*
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Plasmids / metabolism
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Protein Structure, Tertiary
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Protein-Serine-Threonine Kinases / metabolism
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RNA, Small Interfering / metabolism
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Signal Transduction
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TNF Receptor-Associated Factor 3 / metabolism
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TNF Receptor-Associated Factor 6 / metabolism*
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Transcriptional Activation
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Transfection
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Viral Matrix Proteins / chemistry*
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Viral Matrix Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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EBV-associated membrane antigen, Epstein-Barr virus
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Intracellular Signaling Peptides and Proteins
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MYD88 protein, human
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Myeloid Differentiation Factor 88
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NF-kappa B
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RNA, Small Interfering
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TNF Receptor-Associated Factor 3
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TNF Receptor-Associated Factor 6
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Viral Matrix Proteins
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Luciferases
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IRAK1 protein, human
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IRAK4 protein, human
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Interleukin-1 Receptor-Associated Kinases
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Protein-Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7