中科院上海藥物所蔣華良研究員,、羅成副研究員與美國弗吉尼亞聯(lián)邦大學(xué)生化與分子生物學(xué)系Sarah Spiegel教授組成研究團隊,、開展合作研究再結(jié)碩果。繼2009年在《科學(xué)》雜志發(fā)表“鞘氨醇磷酸酯（Sphingosine-1-phosphate, S1P）調(diào)控機制的研究”后,，該研究團隊在該領(lǐng)域再次取得突破性進展,，研究論文于6月24日發(fā)表在英國《自然》雜志上。
相關(guān)閱讀：Science：鞘氨醇磷酸酯調(diào)控機制的研究
該研究綜合運用計算生物學(xué)方法和實驗技術(shù)首次發(fā)現(xiàn)S1P是腫瘤壞死因子受體相關(guān)因子2 (Tumour necrosis factor (TNF) receptor-associated factor 2, TRAF2) 生理調(diào)節(jié)輔助因子,。S1P最初發(fā)現(xiàn)與細胞生長的調(diào)節(jié)有關(guān),，它是一種存在于細胞核中具有生物活性的脂質(zhì)信使，由鞘氨醇激酶亞型1（SphK1）產(chǎn)生,。S1P通過TRAF2調(diào)控TNF-a和NF-кB信號通路,，進而參與一系列炎癥、抗凋亡和免疫反應(yīng),。
生物谷啟用新域名 www.bioon.net
該研究還闡明了S1P調(diào)控NF-кB信號通路的機制：S1P通過特異性結(jié)合在TRAF2的N-末端RING功能域上,，激活其E3泛素化連接酶活性，進而催化完成RIP1蛋白上63位賴氨酸相連的多泛素化修飾,。泛素化的RIP1可以通過招募并磷酸化激活I(lǐng)KK復(fù)合物,，最終激活NF-кB信號通路。該研究圓滿解釋了SphK1和 S1P如何參與調(diào)控炎癥,、抗凋亡和免疫反應(yīng),，發(fā)揮細胞保護作用的機制，揭開了科學(xué)家長期探索的謎底,。
該研究團隊綜合運用理論和實驗的手段研究生命科學(xué)復(fù)雜問題,，表明理論科學(xué)與實驗科學(xué)的有效整合，將極大地促進生命科學(xué)相關(guān)關(guān)鍵問題的研究,。
該研究得到了科技部973計劃項目,、新藥研究國家重點實驗室的部分資助。(生物谷www.Bioon.net)
生物谷推薦原文出處：
Nature doi:10.1038/nature09128
Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
Sergio E. Alvarez,Kuzhuvelil B. Harikumar,Nitai C. Hait,Jeremy Allegood,Graham M. Strub,Eugene Y. Kim,Michael Maceyka,Hualiang Jiang,Cheng Luo,Tomasz Kordula,Sheldon Milstien& Sarah Spiegel
Tumour-necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is a key component in NF-κB signalling triggered by TNF-α1, 2. Genetic evidence indicates that TRAF2 is necessary for the polyubiquitination of receptor interacting protein 1 (RIP1)3 that then serves as a platform for recruitment and stimulation of IκB kinase, leading to activation of the transcription factor NF-κB. Although TRAF2 is a RING domain ubiquitin ligase, direct evidence that TRAF2 catalyses the ubiquitination of RIP1 is lacking. TRAF2 binds to sphingosine kinase 1 (SphK1)4, one of the isoenzymes that generates the pro-survival lipid mediator sphingosine-1-phosphate (S1P) inside cells. Here we show that SphK1 and the production of S1P is necessary for lysine-63-linked polyubiquitination of RIP1, phosphorylation of IκB kinase and IκBα, and IκBα degradation, leading to NF-κB activation. These responses were mediated by intracellular S1P independently of its cell surface G-protein-coupled receptors. S1P specifically binds to TRAF2 at the amino-terminal RING domain and stimulates its E3 ligase activity. S1P, but not dihydro-S1P, markedly increased recombinant TRAF2-catalysed lysine-63-linked, but not lysine-48-linked, polyubiquitination of RIP1 in vitro in the presence of the ubiquitin conjugating enzymes (E2) UbcH13 or UbcH5a. Our data show that TRAF2 is a novel intracellular target of S1P, and that S1P is the missing cofactor for TRAF2 E3 ubiquitin ligase activity, indicating a new paradigm for the regulation of lysine-63-linked polyubiquitination. These results also highlight the key role of SphK1 and its product S1P in TNF-α signalling and the canonical NF-κB activation pathway important in inflammatory, antiapoptotic and immune processes.
