Two Mechanistically and Temporally Distinct NF-
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
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 
B (NF-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-B, their potential functional and physical interactions remain unclear. Here, we showed that TAK1-mediated activation of NF-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-B, TRAF6 subsequently activated NF-B through MEKK3 independently of TAK1, thereby establishing continuous activation of NF-B, which was required for the production of sufficient cytokines. Therefore, we propose that the cooperative activation of NF-B by two mechanistically and temporally distinct MEKK3-dependent pathways that diverge at TRAF6 critically contributes to immune and inflammatory systems.
To whom correspondence should be addressed. E-mail: jun-i{at}ims.u-tokyo.ac.jp
