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Polyisoprenyl phosphates in intracellular signalling

Nature volume 389, pages 985–990 (1997)Cite this article

Abstract

In response to environmental stimuli, leukocyte membrane remodelling generates biologically active lipids that can serve as both intra- and extracellular mediators1. There are several classes of lipids that can mediate inflammatory reactions.1 We report here on a new intracellular lipid signal that regulates oxygen-radical formation in neutrophils, a key response in microbial killing, inflammation and tissue injury. Screening of neutrophil-derived extracts rich in phosphorylated, non-saponifiable lipids revealed a potent inhibitor of superoxide anion (O2−) production. Structural analysis of biologically active fractions gave four major phosphorylated lipids: most abundant was presqualene diphosphate (PSDP). Upon activation of neutrophil receptors, PSDP and its monophosphate form, presqualene monophosphate (PSMP), undergo rapid remodelling. At submicromolar concentrations, PSDP but not PSMP inhibit O2− production by human neutrophil cell-free oxidase preparations. We prepared PSDP and PSMP by total organic synthesis and matched both the physical properties and biological activity of the neutrophil-derived compounds. Our results indicate that PSDP, a recognized intermediate of cholesterol biosynthesis2, is present in immune effector cells and is a potent regulator of the cellular response in host defence.

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Figure 1: Neutrophil-derived lipids that resist saponification regulate superoxide anion generated by neutrophil sonicates.
Figure 2: Elucidation of phosphorylated neutrophil lipids that resist saponification.
Figure 3: Receptor activation triggers remodelling of compound II and compound IV.
Figure 4: PSDP selectively inhibits neutrophil superoxide anion generation.
Figure 5: Scheme for polyisoprenyl phosphate remodelling.

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References

  1. Serhan, C. N., Haeggström, J. Z. & Leslie, C. C. Lipid mediator networks in cell signaling: Update and impact of cytokines. FASEB J. 10, 1147 –1158 (1996).

    Article  CAS  Google Scholar 

  2. Jarstfer, M. B., Blagg, B. S. J., Rogers, D. H. & Poulter, C. D. Biosynthesis of squalene. Evidence for a tertiary cyclopropylcarbinyl cationic intermediate in the rearrangement of presqualene diphosphate to squalene. J. Am. Chem. Soc. 118, 13089– 13090 (1996).

    Article  CAS  Google Scholar 

  3. Weissmann, G., Smolen, J. E. & Korchak, H. M. Release of inflammatory mediators from stimulated neutrophils. N. Engl. J. Med. 303, 27– 34 (1980).

    Article  CAS  Google Scholar 

  4. Adair, W. L. & Keller, R. K. Isolation and assay of dolichol and dolichyl phosphate. Meth. Enzymol. 111, 201–215 (1985).

    Article  CAS  Google Scholar 

  5. Van Dessel, G. A. F., Lagrou, A. R., Hilderson, H. J. J. & Dierick, W. S. H. in CRC Handbook of Chromatography (eds Mukherjee, K. D., Weber, N. & Sherma, J.) 321–337 (CRC Press, Boca Raton, (1993)).

    Google Scholar 

  6. McPhail, L. C., Shirley, P. S., Clayton, C. C. & Synderman, R. Activation of the respiratory burst enzyme from human neutrophils in a cell-free system. Evidence for a soluble cofactor. J. Clin. Invest. 75, 1735–1739 (1985).

    Article  CAS  Google Scholar 

  7. Agwu, D. E., McPhail, L. C., Sozzani, S., Bass, D. A. & McCall, C. E. Phosphatidic acid as a second messenger in human polymorphonuclear keukocytes. Effects on activation of NADPH oxidase. J. Clin. Invest. 88, 531– 539 (1991).

    Article  CAS  Google Scholar 

  8. Bokoch, G. M. & Knaus, U. G. Ras-related GTP-binding proteins and leukocyte signal transduction. Curr. Opin. Hematol. 1, 53–60 (1994).

    CAS  PubMed  Google Scholar 

  9. Farnsworth, C. C., Gelb, M. H. & Glomset, J. A. Identification of geranylgeranyl-modified proteins in HeLa cells. Science 247, 320– 322 (1990).

    Article  ADS  CAS  Google Scholar 

  10. Popják, G., Edmond, J., Clifford, K. & Williams, V. Biosynthesis and structure of a new intermediate between farnesyl pyrophosphate and squalene. J. Biol. Chem. 244, 1897– 1918 (1969).

    PubMed  Google Scholar 

  11. Epstein, W. W. & Rilling, H. C. Studies on the mechanism of squalene biosynthesis. The structure of presqualene pyrophosphate. J. Biol. Chem. 245, 4597– 4605 (1970).

    CAS  PubMed  Google Scholar 

  12. Goldstein, J. L. & Brown, M. S. Regulation of the mevalonate pathway. Nature 343, 425– 430 (1990).

    Article  ADS  CAS  Google Scholar 

  13. Corey, E. J. & Volante, R. P. Application of unreactive analogs of terpenoid pyrophosphates to studies of multistep biosynthesis. Demonstration that “presqualene pyrophosphate” is an essential intermediate on the path to squalene. J. Am. Chem. Soc. 98, 1291–1293 (1976).

    Article  CAS  Google Scholar 

  14. Mookhtiar, K. A., Kalinowski, S. S., Khang, D. & Poulter, C. D. Yeast squalene synthase. A mechanism for addition of substrates and activation by NADPH. J. Biol. Chem. 269, 11201– 11207 (1994).

    CAS  PubMed  Google Scholar 

  15. Shechter, I., Fogelman, A. M. & Popjak, G. Adeficiency of mixed function oxidase activities in the cholesterol biosynthetic pathway of human granulocytes. J. Lipid Res. 21, 277–283 ( 1980).

    CAS  PubMed  Google Scholar 

  16. Philips, M. R. et al. Carboxyl methylation of ras-related proteins during signal transduction in neutrophils. Science 259, 977–980 (1992).

    Article  ADS  Google Scholar 

  17. Baggiolini, M., Boulay, F., Badwey, J. A. & Curnutte, J. T. Activation of neutrophil leukocytes: chemoattractant receptors and respiratory burst. FASEB J. 7, 1004– 1010 (1993).

    Article  CAS  Google Scholar 

  18. Gomez-Cambronero, J. & Sha'afi, R. I. in Cell–Cell Interactions in the Release of Inflammatory Mediators (eds Wong, P. Y.-K. & Serhan, C. N.) 35–71 (Plenum, New York, (1991)).

    Book  Google Scholar 

  19. Scheer, A. & Gierschik, P. S-prenylated cysteine analogues inhibit receptor-mediated G protein activation in native human granulocyte and reconstituted bovine retinal rod outer segment membranes. Biochemistry 34, 4952–4961 (1995).

    Article  CAS  Google Scholar 

  20. Simons, K. & Ikonen, E. Functional rafts in cell membranes. Nature 387, 569–572 (1997).

    Article  ADS  CAS  Google Scholar 

  21. Rogers, D. H., Yi, E. C. & Poulter, C. D. Enantioselective synthesis of (+)-presqualene diphosphate. J. Org. Chem. 60, 941– 945 (1995).

    Article  CAS  Google Scholar 

  22. Quinn, M. T. Low-molecular-weight GTP-binding proteins and leukocyte signal transduction. J. Leuk. Biol. 58, 263– 276 (1995).

    Article  CAS  Google Scholar 

  23. Maddox, J. F. & Serhan, C. N. Lipoxin A4and B 4are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction. J. Exp. Med. 183, 137–146 (1996).

    Article  CAS  Google Scholar 

  24. Chen, P. S., Toribara, T. Y. & Warner, H. Microdetermination of phosphorus. Analyt. Chem. 28, 1756–1758 ( 1956).

    Article  CAS  Google Scholar 

  25. Tou, J. & Dola, T. Leukotriene B4stimulation of an early elevation of phosphatidic acid mass in human neutrophils. Lipids 30, 373–381 ( 1995).

    Article  CAS  Google Scholar 

  26. Bromberg, Y. & Pick, E. Unsaturated fatty acids stimulate NADPH-dependent superoxide production by cell-free system derived from macrophages. Cell. Immunol. 88, 213–221 (1984).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by the NIH (GM & NIDDK) and a basic discovery research grant from ONO Pharmaceuticals to C.N.S. and the NIH (GM) to N.A.P. B.D.L. was supported in part by a Paul Dudley White postdoctoral fellowship of the Massachusetts Affiliate, American Heart Association. We thank Valery V. Fokin for help with the synthesis and the NMR analyses of PSDP and PSMP.

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  1. Charles N. Serhan: Correspondence and requests for materials should be addressed to C.N.S.

Authors and Affiliations

  1. Department of Anesthesia, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, 02115, Massachusetts, USA

    Bruce D. Levy & Charles N. Serhan

  2. Department of Chemistry, University of Southern California, Los Angeles, 90089, California, USA

    Nicos A. Petasis

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  1. Bruce D. Levy
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Correspondence to Charles N. Serhan.

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Levy, B., Petasis, N. & Serhan, C. Polyisoprenyl phosphates in intracellular signalling. Nature 389, 985–990 (1997). https://doi.org/10.1038/40180

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