日本专家在新一期英国《自然—细胞生物学》杂志上发表论文说，他们发现了促使核转录因子NF—κB活跃的机制。这种核转录因子过度活跃可导致特应性皮炎、癌症等疾病，这项成果有望成为开发相关新药的线索。
NF—κB核转录因子通常在细胞浆中与某些抑制蛋白结合，呈无活性状态。日本大阪大学的生物化学教授岩井一宏等研究人员，以人体中分解无用蛋白的泛素为研究对象，通过小鼠细胞实验发现几个泛素分子连接而成的聚泛素与另一种蛋白相结合，可以使NF—κB核转录因子开始活跃起来。
目前用于抑制NF—κB核转录因子活性的药物有类固醇制剂等，但是这类药物同时也作用于其他蛋白，由此会引发多种副作用。而岩井一宏等人的实验显示，聚泛素似乎只作用于NF—κB核转录因子。这些研究人员认为，找到抑制聚泛素作用的物质，有望为开发副作用小的相关药物创造可能性。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature Cell Biology，doi:10.1038/ncb1821，Fuminori Tokunaga，Kazuhiro Iwai
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.
