日本專家在新一期英國《自然—細(xì)胞生物學(xué)》雜志上發(fā)表論文說，他們發(fā)現(xiàn)了促使核轉(zhuǎn)錄因子NF—κB活躍的機(jī)制,。這種核轉(zhuǎn)錄因子過度活躍可導(dǎo)致特應(yīng)性皮炎,、癌癥等疾病，這項(xiàng)成果有望成為開發(fā)相關(guān)新藥的線索,。

NF—κB核轉(zhuǎn)錄因子通常在細(xì)胞漿中與某些抑制蛋白結(jié)合,，呈無活性狀態(tài)。日本大阪大學(xué)的生物化學(xué)教授巖井一宏等研究人員,，以人體中分解無用蛋白的泛素為研究對象,，通過小鼠細(xì)胞實(shí)驗(yàn)發(fā)現(xiàn)幾個(gè)泛素分子連接而成的聚泛素與另一種蛋白相結(jié)合，可以使NF—κB核轉(zhuǎn)錄因子開始活躍起來,。

目前用于抑制NF—κB核轉(zhuǎn)錄因子活性的藥物有類固醇制劑等,，但是這類藥物同時(shí)也作用于其他蛋白,，由此會(huì)引發(fā)多種副作用。而巖井一宏等人的實(shí)驗(yàn)顯示,，聚泛素似乎只作用于NF—κB核轉(zhuǎn)錄因子,。這些研究人員認(rèn)為，找到抑制聚泛素作用的物質(zhì),，有望為開發(fā)副作用小的相關(guān)藥物創(chuàng)造可能性,。（生物谷Bioon.com）

生物谷推薦原始出處：

Nature Cell Biology，doi:10.1038/ncb1821,，F(xiàn)uminori 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.