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Involvement of linear polyubiquitylation of NEMO in NF-κB activation
Fuminori Tokunaga1,2,3, Shin-ichi Sakata1,2,3, Yasushi Saeki4, Yoshinori Satomi5, Takayoshi Kirisako3, Kiyoko Kamei1,3, Tomoko Nakagawa1,3, Michiko Kato3, Shigeo Murata4,6, Shoji Yamaoka7, Masahiro Yamamoto8, Shizuo Akira9, Toshifumi Takao5, Keiji Tanaka4 & Kazuhiro Iwai1,2,3
Nuclear factor-B (NF-κB) is a key transcription factor in inflammatory, anti-apoptotic and immune processes. The ubiquitin pathway is crucial in regulating the NF-κB pathway. We have found that the LUBAC ligase complex, composed of the two RING finger proteins HOIL-1L and HOIP, conjugates a head-to-tail-linked linear polyubiquitin chain to substrates. Here, we demonstrate that LUBAC activates the canonical NF-κB pathway by binding to NEMO (NF-κB essential modulator, also called IKK) and conjugates linear polyubiquitin chains onto specific Lys residues in the CC2–LZ domain of NEMO in a Ubc13-independent manner. Moreover, in HOIL-1 knockout mice and cells derived from these mice, NF-κB signalling induced by pro-inflammatory cytokines such as TNF- and IL-1 was suppressed, resulting in enhanced TNF-–induced apoptosis in hepatocytes of HOIL-1 knockout mice. These results indicate that LUBAC is involved in the physiological regulation of the canonical NF-κB activation pathway through linear polyubiquitylation of NEMO.
1 Department of Biophysics and Biochemistry, Graduate School of Medicine and Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
CREST, Japan Science Technology Corporation, Kawaguchi, Saitama 332-0012, Japan.
2 Department of Molecular Cell Biology, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka 545-8585
3 Laboratory of Frontier Science, Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan.
4 Laboratory of Protein Profiling and Functional Proteomics, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
5 Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
6 Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
7 Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine
8 Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan.
