Recently, one research team consists of Professor Hua-liang Jiang and Associate Professor Cheng Luo in Shanghai Institute of Materia Medica and Professor Sarah Spiegel from the Department of Biochemistry and Molecular Biology of Virginia Commonwealth University harvest progress on the signaling pathway regulated by Sphingosine-1-phosphate (S1P) again. Following the study entitled “Regulation of Histone Acetylation in the Nucleus by sphingosine-1-Phosphate” published in Science magazine in 2009, the research team made the breakthrough again on this field. Their study was reported in the Nature magazine in June 24, 2010. (Nature, 2010, 465, 1084-8)

In this study, they first demonstrated that S1P is a missing cofactor for the E3 ubiquitin ligase TRAF2 (Tumour related associated factor 2) by using of computational biology methods and experimental technique. S1P is a sphingolipid metabolite present in the nucleus which is generated by sphingosine kinase 1, while it was originally identified in regulating cell growth. S1P regulate TNF-aand NF-кB signaling pathway by TRAF2, and then participate in a series of cellular and physiological processes, including inflammatory,　anti-apoptosis,　and immune responses. In this study, they illustrate the mechanism regulated by S1P in NF-кB signaling pathway: S1P specifically binds to TRAF2 at the N-terminal RING domain and stimulates its E3 ubiquitin ligase activity, and then catalyze the RIP1-lysine-63-linked to multiple ubiquitin modification. The ubiquitination of RIP1 may activate IKK complex by recruitment and phosphorylation. Ultimately, it may activate the NF-кB signaling pathway. Moreover, the study also successfully explain that how the Sphk1 and S1P participate in regulation of inflammation, apoptosis and immune responses, and play a crucial role in the cell protective mechanism, which is a mystery for a long time.

Meanwhile, the successful strategy by this research team to combine theoretical with experimental approaches to explore the complicated questions in biological science indicates that the strategy will accelerate the study for the key questions in Life Science.

This study is partially supported by the People’s Republic of China Ministry of Science and Technology (973 program) and the State Key Laboratory of Drug Research.

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The binding mode of S1P into the pocket of the RING domain of TRAF2. Surface contour of the binding site with S1P was coloured by electrostatic potential

A model of the role of SphK1 and S1P in TRAF2 actions and regulation of NF-k B activation and the anti-apoptotic program initiated by TNF