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Sci. Signal., 20 October 2009
Vol. 2, Issue 93, p. ra66
[DOI: 10.1126/scisignal.2000387]


Two Mechanistically and Temporally Distinct NF-{kappa}B Activation Pathways in IL-1 Signaling

Kohsuke Yamazaki1, Jin Gohda1, Atsuhiro Kanayama2*, Yusei Miyamoto2, Hiroaki Sakurai3, Masahiro Yamamoto4, Shizuo Akira5, Hidetoshi Hayashi6, Bing Su7, and Jun-ichiro Inoue1{dagger}

1 Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
2 Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba 277-8562, Japan.
3 Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.
4 Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
5 Laboratory of Host Defense, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
6 Department of Drug Metabolism and Disposition, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya 467-8603, Japan.
7 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520–8089, USA.

* Present address: Department of Global Infectious Diseases and Tropical Medicine, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.

Abstract: The cytokine interleukin-1 (IL-1) mediates immune and inflammatory responses by activating the transcription factor nuclear factor {kappa}B (NF-{kappa}B). Although transforming growth factor–β–activated kinase 1 (TAK1) and mitogen-activated protein kinase (MAPK) kinase kinase 3 (MEKK3) are both crucial for IL-1–dependent activation of NF-{kappa}B, their potential functional and physical interactions remain unclear. Here, we showed that TAK1-mediated activation of NF-{kappa}B 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-{kappa}B, TRAF6 subsequently activated NF-{kappa}B through MEKK3 independently of TAK1, thereby establishing continuous activation of NF-{kappa}B, which was required for the production of sufficient cytokines. Therefore, we propose that the cooperative activation of NF-{kappa}B by two mechanistically and temporally distinct MEKK3-dependent pathways that diverge at TRAF6 critically contributes to immune and inflammatory systems.

{dagger} To whom correspondence should be addressed. E-mail: jun-i{at}

Citation: K. Yamazaki, J. Gohda, A. Kanayama, Y. Miyamoto, H. Sakurai, M. Yamamoto, S. Akira, H. Hayashi, B. Su, J.-i. Inoue, Two Mechanistically and Temporally Distinct NF-{kappa}B Activation Pathways in IL-1 Signaling. Sci. Signal. 2, ra66 (2009).

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