Two mechanistically and temporally distinct NF-kappaB activation pathways in IL-1 signaling.
The cytokine interleukin-1 (IL-1) mediates immune and inflammatory responses by activating the transcription factor nuclear factor kappaB (NF-kappaB). Although transforming growth factor-beta-activated kinase 1 (TAK1) and mitogen-activated protein kinase (MAPK) kinase kinase 3 (MEKK3) are both crucial for IL-1-dependent activation of NF-kappaB, their potential functional and physical interactions remain unclear. Here, we showed that TAK1-mediated activation of NF-kappaB required the transient formation of a signaling complex that included tumor necrosis factor receptor-associated factor 6 (TRAF6), MEKK3, and TAK1. Site-specific, lysine 63-linked polyubiquitination of TAK1 at lysine 209, likely catalyzed by TRAF6 and Ubc13, was required for the formation of this complex. After TAK1-mediated activation of NF-kappaB, TRAF6 subsequently activated NF-kappaB through MEKK3 independently of TAK1, thereby establishing continuous activation of NF-kappaB, which was required for the production of sufficient cytokines. Therefore, we propose that the cooperative activation of NF-kappaB by two mechanistically and temporally distinct MEKK3-dependent pathways that diverge at TRAF6 critically contributes to immune and inflammatory systems.
Yamazaki
Kohsuke
K
Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Gohda
Jin
J
Kanayama
Atsuhiro
A
Miyamoto
Yusei
Y
Sakurai
Hiroaki
H
Yamamoto
Masahiro
M
Akira
Shizuo
S
Hayashi
Hidetoshi
H
Su
Bing
B
Inoue
Jun-ichiro
J
D000818:Animals; D002460:Cell Line; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000172:deficiency / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7
D007375:Interleukin-1; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D044763:Ubiquitin-Conjugating Enzymes; D000099151:MAP Kinase Kinase Kinase 7; C514982:Ube2n protein, mouse; C482626:Map3k3 protein, mouse