鞘氨醇磷酸酯调控机制的研究进展

ADVANCE IN THE STUDY OF THE MECHANISMS REGULATED BY SPHINGOSINE-1-PHOSPHATE

鞘氨醇磷酸酯(Sphingosine-1-phosphate,S1P)是一种存在于细胞中具有生物活性的脂质信使,关于这类脂质信使在核内如何调控基因表达及在细胞质中如何调控NF-κB信号通路机制尚未明确。国家自然科学基金项目承担者、上海药物研究所罗成副研究员与美国弗吉尼亚联邦大学Sarah Spiegel教授开展合作研究,在该领域研究连续取得重大突破。2009年9月,该研究团队在《科学》(Science)杂志首次提出S1P是一种组蛋白去乙酰化酶(Histone deacetylase,HDAC)内源性生理调节因子,HDAC是S1P在核内的直接作用靶标,S1P通过调控HDAC,进而达到调控基因表达的功能。2010年6月24日,该团队在《自然》(Nature)杂志上阐明了S1P在NF-κB信号通路上的调控机制,即TRAF2是S1P在胞内的一个新靶点,S1P是人们一直在探索的激活TRAF2的E3泛素连接酶活性的辅助因子,该研究提供了一个RIP1上K63位多聚泛素化调节的新模式,并且阐明了SphK1及其产物S1P在TNF-α信号通路和经典的NF-κB信号通路中的关键作用。S1P在调控基因表达和TNF-α信号通路和经典的NF-κB信号通路中的关键作用的新机制将为发展新型HDAC抑制剂,开发抗肿瘤、炎症及免疫疾病的新型药物提供新的关键线索。

Sphingosine-1-phosphate （S1P） is a bioactive lipid messenger in the cells that regulate gene expression and NF-κB signal pathway through unknown mechanisms. Recently, Cheng Luo, Associate Professor of DDDC in Shanghai Institute of Materia Medica, whose project was funded by the National Natural Science Foundation of China, joined in a research team led by Professor Sarah Spiegel of Virginia Commonwealth University. The team continuously made significant breakthroughs in understanding the regulation mechanism of Sphingosine-1-Phosphate. In September 2009, in a paper published on Science magazine （Science, 2009, 325. 1254 1257）, they firstly demonstrated that S1P is a physiologically important regulator of histone deacetylases （HDACs）, HDACs are direct intracellular targets of S1P. Furthermore, they identified the mechanism that S1P regulates gene expression through regulating the activity of HDACs. In June 24th, 2010, in another paper to be published on Nature magazine （Nature, 2010, June 24th, advance on- line publication, doi. 10. 1038/nature09128） which reports the regulation of NF-κB signaling pathway by S1P. They demonstrate that S1P is the missing cofactor for TRAF2 （tumour-necrosis factor receptor-associated factor 2） and indicate a new paradigm for the regulation of lysine-63-linked poly-ubiquitination. The study also highlight the key role of SphK1 and its product S1P in TNF-α signalling and the canonical NF-κB activation pathway, and then play crucial role in inflammatory, antiapoptotic and immune processes. The identification of new mechanisms by which S1P regulates gene expression and TNF and NF-κB signaling pathway will light up the road to develop novel inhibitors that might be useful for treatment of cancer and inflammatory diseases.