The C-terminal activating region 2 of the Epstein-Barr virus-encoded latent membrane protein 1 activates NF-kappaB 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-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).
Wu
Liming
L
Department of Biochemistry, Hong Kong University of Science & Technology, Clearwater Bay, Kowloon, Hong Kong, China.
Nakano
Hiroyasu
H
Wu
Zhenguo
Z
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D051550:I-kappa B Kinase; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D014763:Viral Matrix Proteins; D000099151:MAP Kinase Kinase Kinase 7; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C507779:MYD88 protein, human; C507768:IRAK1 protein, human; C507773:IRAK4 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human