Lipid signaling: S1P's nuclear program

Lipidomics Gateway (23 September 2009) [doi:10.1038/lipidmaps.2009.26]

Sphingosine-1-phosphate binds to and inhibits histone deacetylases 1 and 2, and regulates gene expression.

Many cellular processes are mediated by binding of the small, bioactive phospholipid sphingosine-1-phosphate (S1P) to its dedicated cell-surface receptors. Produced intracellularly by two sphingosine kinase isoenzymes, SphK1 and SphK2, S1P is soluble and is secreted into the extracellular space. Some effects of S1P are independent of its receptors, and might initiate inside the cell, but although enzymes that control sphingolipid metabolism are found in the nucleus, no intracellular S1P targets have been identified. Reporting in Science, Sarah Spiegel and colleagues now emphatically confirm that S1P does have an active intracellular role. Nuclear SphK2 associates with histones, producing S1P that binds to and inhibits the histone deacetylases HDAC1 and HDAC2, resulting in enhanced local histone acetylation and increased transcription of target genes.

Much more is known about the functions of SphK1 than SphK2. As the latter enzyme localizes to the nucleus, or shuttles between the nucleus and cytosol, Spiegel and colleagues sought to determine its function there. In nuclear extracts from breast cancer cells, overexpression of SphK2 significantly increased the levels of S1P, confirming that the kinase is active in the nucleus. The endogenous protein was present in the chromatin fraction and in purified mononucleosomes, suggesting an association with histones. Accordingly, overexpressed SphK2, but not SphK1, coimmunoprecipitated from nuclear extracts with histone H3.

In vitro, immobilized SphK2 bound purified histone H3, but not H4, H2B or H2A. Catalytically inactive SphK2 was also able to bind H3, but it had no effect on histone acetylation. By contrast, the active enzyme increased the acetylation of specific histone lysine residues: H3-K9, H4-K5 and H2B-K12. Adding S1P to nuclear extracts replicated this pattern, whereas siRNA targeted to SphK2 had the opposing effect.

The acetylation of histone lysines is critical for the epigenetic control of transcription. Histone acetyltransferases (HATs) and deacetylases (HDACs) determine histone acetylation levels, but in nuclear extracts neither S1P nor SphK2 increased HAT activity. By contrast, S1P inhibited the activity of HDAC1 and HDAC2. S1P in vitro was almost as effective as the HDAC inhibitor TSA, and TSA displaced radiolabeled S1P from the HDAC active site.

Next, the authors investigated whether external signals can alter transcription by influencing HDAC activity through changes to nuclear S1P levels. Treatment of cells with PMA— a protein kinase C activator that enhances SphK2 activation — rapidly induced elevation of S1P in the nucleus, accompanied by HDAC inhibition. Furthermore, chromatin immunoprecipitation analysis showed that SphK2 is present at the promoter sequence of p21 and c-Fos, two PMA-responsive genes that are also known to be induced by inhibition of HDAC1 or HDAC2.

This study introduces a potentially important role for SphK2 and S1P in the nucleus. Inhibition of HDACs adds to the multi-feathered cap of S1P signaling, and increases our understanding of nuclear lipid functions. Further work will define which genes are responsive to S1P, and what the implications may be for human diseases such as cancer.

Emma Leah

- Copyright © 2009 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission


  1. Hait, N. C., Allegood, J., Maceyka, M., Strub, G. M., Harikumar, K. B., Singh, S. K., Luo, C., Marmorstein, R., Kordula, T., Milstien, S. and Spiegel, S. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate.

    Science 325, 1254-1257 (2009). doi:10.1126/science.1176709

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