TAK1 is a component of the Epstein-Barr virus LMP1 complex and is essential for activation of JNK but not of NF-kappaB.
Epstein-Barr virus latent membrane protein 1 (LMP1) activates NF-kappaB and c-Jun N-terminal kinase (JNK), which is essential for LMP1 oncogenic activity. Genetic analysis has revealed that tumor necrosis factor receptor-associated factor 6 (TRAF6) is an indispensable intermediate of LMP1 signaling leading to activation of both NF-kappaB and JNK. However, the mechanism by which LMP1 engages TRAF6 for activation of NF-kappaB and JNK is not well understood. Here we demonstrate that TAK1 mitogen-activated protein kinase kinase kinase and TAK1-binding protein 2 (TAB2), together with TRAF6, are recruited to LMP1 through its N-terminal transmembrane region. The C-terminal cytoplasmic region of LMP1 facilitates the assembly of this complex and enhances activation of JNK. In contrast, IkappaB kinase gamma is recruited through the C-terminal cytoplasmic region and this is essential for activation of NF-kappaB. Furthermore, we found that ablation of TAK1 resulted in the loss of LMP1-induced activation of JNK but not of NF-kappaB. These results suggest that an LMP1-associated complex containing TRAF6, TAB2, and TAK1 plays an essential role in the activation of JNK. However, TAK1 is not an exclusive intermediate for NF-kappaB activation in LMP1 signaling.
Uemura
Noriyuki
N
Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan.
Kajino
Taisuke
T
Sanjo
Hideki
H
Sato
Shintaro
S
Akira
Shizuo
S
Matsumoto
Kunihiro
K
Ninomiya-Tsuji
Jun
J
D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D014162:Transfection; D014763:Viral Matrix Proteins / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D004791:Enzyme Inhibitors; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D014763:Viral Matrix Proteins; D000099151:MAP Kinase Kinase Kinase 7; C037662:EBV-associated membrane antigen, Epstein-Barr virus