中科院上海藥物所蔣華良研究員、羅成副研究員與美國維吉尼亞聯邦大學生化與分子生物學系Sarah Spiegel教授組成研究團隊、開展合作研究再結碩果。繼2009年在《科學》雜誌發表「鞘氨醇磷酸酯（Sphingosine-1-phosphate, S1P）調控機制的研究」後，該研究團隊在該領域再次取得突破性進展，研究論文於6月24日發表在英國《自然》雜誌上。
相關閱讀：Science：鞘氨醇磷酸酯調控機制的研究
該研究綜合運用計算生物學方法和實驗技術首次發現S1P是腫瘤壞死因子受體相關因子2 (Tumour necrosis factor (TNF) receptor-associated factor 2, TRAF2) 生理調節輔助因子。S1P最初發現與細胞生長的調節有關，它是一種存在於細胞核中具有生物活性的脂質信使，由鞘氨醇激酶亞型1（SphK1）產生。S1P通過TRAF2調控TNF-a和NF-кB信號通路，進而參與一系列炎症、抗凋亡和免疫反應。
生物谷啟用新域名 www.bioon.net
該研究還闡明了S1P調控NF-кB信號通路的機制：S1P通過特異性結合在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可以通過招募並磷酸化激活IKK複合物，最終激活NF-кB信號通路。該研究圓滿解釋了SphK1和 S1P如何參與調控炎症、抗凋亡和免疫反應，發揮細胞保護作用的機制，揭開了科學家長期探索的謎底。
該研究團隊綜合運用理論和實驗的手段研究生命科學複雜問題，表明理論科學與實驗科學的有效整合，將極大地促進生命科學相關關鍵問題的研究。
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.