Role of Ceramide in CD95 Signaling

  • Volker Teichgräber
  • Gabriele Hessler
  • Erich Gulbins
Part of the Medical Intelligence Unit book series (MIUN)


Recent studies indicate that the reorganization of receptor molecules in distinct domains of the cell membrane constitutes an important and general mechanism that is required for the initiation of signaling via various receptor molecules. Studies on the CD95 receptor might serve as a paradigm for the mechanism mediating receptor clustering/aggregation. These studies revealed activation of the acid sphingomyelinase and a release of ceramide in the outer leaflet of the cell membrane upon stimulation of CD95. The unique biophysical properties of ceramide trigger the formation of large ceramide-enriched membrane platforms that serve to trap and cluster the receptor. This process results in a high density of CD95 within a distinct area of the cell membrane and amplifies the primary signal generated by binding of the CD95 ligand and, thus, permits the induction of apoptosis. Furthermore, ceramide-enriched membrane domains mediate the assembling of the receptor with intracellular signaling molecules, in particular FADD, caspase 8, and the potassium channel Kvl.3 that finally mediate apoptosis initiated by CD95 ligation.


Lipid Raft Receptor Molecule Membrane Raft CD95 Ligation Acid Sphingomyelinase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Singer SJ, Nicolson GL. The fluid mosaic model of the structure of cell membranes. Science 1972; 175:720–731.PubMedCrossRefGoogle Scholar
  2. 2.
    Simons K, Ikonen E. Functional rafts in cell membranes. Nature 1997; 387:569–572.PubMedCrossRefGoogle Scholar
  3. 3.
    Brown DA, London E. Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 1998; 14:111–167.PubMedCrossRefGoogle Scholar
  4. 4.
    Andersen RG. The caveolae membrane system. Annu Rev Biochem 1998; 67:199–225.CrossRefGoogle Scholar
  5. 5.
    Harder T, Simons K. Caveolae, DIGs, and the dynamics of sphingolipid-cholesterol microdomains. Curr Opin Cell Biol 1997; 9:534–542.PubMedCrossRefGoogle Scholar
  6. 6.
    Heerklotz H. Triton promotes domain formation in lipid raft mixtures. Biophys J 2002; 83:2693–2701.PubMedGoogle Scholar
  7. 7.
    Mayor S, Maxfield FR. Insolubility and redistribution of GPI-anchored proteins at the cell surface after detergent treatment. Mol Biol Cell 1995; 6:929–944.PubMedGoogle Scholar
  8. 8.
    Schuchman EH, Suchi M, Takahashi T et al. Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J Biol Chem 1991; 266:8531–8539.PubMedGoogle Scholar
  9. 9.
    Schissel SL, Jiang X, Tweedie-Hardman J et al. Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J Biol Chem 1998; 273:2738–2746.PubMedCrossRefGoogle Scholar
  10. 10.
    Duan RD, Hertervig E, Nyberg L et al. Distribution of alkaline sphingomyelinase activity in human beings and animals. Tissue and species differences. Dig Dis Sci 1996; 41:1801–1806.PubMedCrossRefGoogle Scholar
  11. 11.
    Grassiné H, Jekle A, Riehle A et al. CD95 signaling via ceramide-rich membrane rafts. J Biol Chem 2001; 276:20589–20596.CrossRefGoogle Scholar
  12. 12.
    Grassmé H, Schwarz H, Gulbins E. Surface ceramide mediates CD95 clustering. Biochem Biophys Res Commun 2001; 284:1016–1030.PubMedCrossRefGoogle Scholar
  13. 13.
    Cremesti A, Paris F, Grassmé H et al. Ceramide enables Fas to cap and kill. J Biol Chem 2001; 276:23954–23961.PubMedCrossRefGoogle Scholar
  14. 14.
    Grassmé H, Jendrossek V, Riehle A et al. Ceramide-rich membrane rafts mediate CD40 clustering. J Immunol 2001; 168:298–307.Google Scholar
  15. 15.
    Grassmé H, Jendrossek V, Riehle A et al. Host defense against P. aeruginosa requires ceramide-rich membrane rafts. Nat Med 2003; 9:322–330.PubMedCrossRefGoogle Scholar
  16. 16.
    Qiu H, Edmunds T, Baker-Malcolm J et al. Activation of human acid sphingomyelinase through modification or deletion of C-terminal cysteine. J Biol Chem 2003; 278:32744–32752.PubMedCrossRefGoogle Scholar
  17. 17.
    Kolzer M, Arenz C, Ferlinz K et al. Phosphatidylinositol-3,5-Bisphosphate is a potent and selective inhibitor of acid sphingomyelinase. Biol Chem 2003; 384:1293–1298.PubMedCrossRefGoogle Scholar
  18. 18.
    Emmelot P, Van Hoeven RP. Phospholipid unsaturation and plasma membrane organization. Chem Phys Lipids 1975; 14:236–246.PubMedCrossRefGoogle Scholar
  19. 19.
    Kolesnick RN, Goni FM, Alonso A. Compartmentalization of ceramide signaling: Physical foundations and biological effects. J Cell Physiol 2000; 184:285–300.PubMedCrossRefGoogle Scholar
  20. 20.
    Holopainen JM, Subramanian M, Kinnunen PK. Sphingomyelinase induces lipid microdomain formation in a fluid phosphatidycholine/sphingomyelin membrane. Biochemistry 1998; 37:17562–17570.PubMedCrossRefGoogle Scholar
  21. 21.
    Nurminen TA, Holopainen JM, Zhao H et al. Observation of topical catalysis by sphingomyelinase coupled to microspheres. J Am Chem Soc 202; 124:12129–12134.Google Scholar
  22. 22.
    Huang HW, Goldberg EM, Zidovetzki R. Ceramides modulate protein kinase C activity and perturb the structure of phosphatidylcholine/ phosphatidylserine bilayers. Biophys J 1999; 77:1489–1497.PubMedGoogle Scholar
  23. 23.
    Veiga MP, Arrondon JL, Goni FM et al. Ceramides in phospholipid membranes: Effects on bilayer stability and transition to nonlamellar phases. Biophys J 1999; 76:342–350.PubMedGoogle Scholar
  24. 24.
    ten Grotenhuis E, Demel RA, Ponec M et al. Phase behavior of stratum corneum lipids in mixed Langmuir-Blodgett monolayers. Biophys J 1996; 71:1389–1399.PubMedCrossRefGoogle Scholar
  25. 25.
    Horinouchi K, Erlich S, Perl DP et al. Acid sphingomyelinase deficient mice: A model of types A and B Niemann-Pick disease. Nat Genet 1995; 10:288–293.PubMedCrossRefGoogle Scholar
  26. 26.
    Callahan JW, Jones CS, Davidson DJ et al. The active site of lysosomal sphingomyelinase: Evidence for the involvement of hydrophobic and ionic groups. J Neurosci Res 1983; 10:151–163.PubMedCrossRefGoogle Scholar
  27. 27.
    Grassmé H, Cremesti A, Kolesnick R et al. Ceramide-mediated clustering is required for CD95-DISC formation. Oncogene 2003; 22:5457–5470.PubMedCrossRefGoogle Scholar
  28. 28.
    Fanzo JC, Lynch MP, Phee H et al. CD95 rapidly clusters in cells of diverse origins. Cancer Biology and Therapy 2003; 2:392–395.PubMedGoogle Scholar
  29. 29.
    Kirschnek S, Paris F, Weller M et al. CD95-mediated apoptosis in vivo involves acid sphingomyelinase. J Biol Chem 2002; 275:27316–27323.Google Scholar
  30. 30.
    Paris F, Grassmé H, Cremesti A et al. Natural ceramide reverses Fas resistance of acid sphingomyelinase (-/-) hepatocytes. J Biol Chem 2000; 276:8297–8305.PubMedCrossRefGoogle Scholar
  31. 31.
    Garcia-Ruiz C, Colell A, Mari M et al. Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J Clin Invest 2003; 111:197–208.PubMedCrossRefGoogle Scholar
  32. 32.
    Schütze S, Potthoff K, Machleidt T et al. TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 1992; 71:765–776.PubMedCrossRefGoogle Scholar
  33. 33.
    Seino KI, Kayagaki N, Takeda K et al. Contribution of Fas ligand to T cell-mediated hepatic injury in mice. Gastroenterology 1997; 113:1315–1322.PubMedCrossRefGoogle Scholar
  34. 34.
    Wang ZQ, Dudhane A, Orlikowski T et al. CD4 engagement induces Fas antigen-dependent apoptosis of T cells in vivo. Eur J Immunol 1994; 24:1549–1552.PubMedCrossRefGoogle Scholar
  35. 35.
    Bock J, Szabò I, Gamper N et al. Ceramide inhibits the potassium channel Kvl.3 by the formation of membrane platforms. Biochem Biophys Res Comm 2003; 305:890–897.PubMedCrossRefGoogle Scholar
  36. 36.
    Hueber AO, Bernard AM, Herincs Z et al. An essential role for membrane rafts in the initiation of Fas/CD95-triggered cell death in mouse thymocytes. EMBO Rep 2002; 3:190–196.PubMedCrossRefGoogle Scholar
  37. 37.
    Garofalo T, Misasi R, Mattei V et al. Association of the death-inducing signaling complex with microdomains after triggering through CD95/Fas. Evidence for caspase-8-ganglioside interaction in T cells. J Biol Chem 2003; 278:8309–8315.PubMedCrossRefGoogle Scholar
  38. 38.
    Scheel-Toellner D, Wang K, Singh R et al. The death-inducing signalling complex is recruited to lipid rafts in Fas-induced apoptosis. Biochem Biophys Res Commun 2002; 297:876–879.PubMedCrossRefGoogle Scholar
  39. 39.
    Delmas D, Rebe C, Lacour S et al. Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. J Biol Chem 2003; 278:41482–41490.PubMedCrossRefGoogle Scholar
  40. 40.
    Gulbins E, Szabo I, Baltzer K et al. Ceramide-induced inhibition of T lymphocyte voltage-gated potassium channel is mediated by tyrosine kinases. Proc Natl Acad Sci USA 1997; 94:7661–7666.PubMedCrossRefGoogle Scholar
  41. 41.
    Bock J, Szabò I, Jekle A et al. Actinomycin D-induced apoptosis involves the potassium channel Kvl.3. Biochem Biophys Res Comm 2002; 295:526–531.PubMedCrossRefGoogle Scholar
  42. 42.
    Bini L, Pacini S, Liberatori S et al. Extensive temporally regulated reorganization of the lipid raft proteome following T-cell antigen receptor triggering. Biochem J 2003; 369:301–309.PubMedCrossRefGoogle Scholar
  43. 43.
    Megha, London E. Ceramide selectively displaces cholesterol from ordered lipid domains (Rafts): Implications for raft structure and function. J Biol Chem 2003 Dec 29 [Epub ahead of print].Google Scholar
  44. 44.
    Bock J, Gulbins E. The transmembranous domain of CD40 determines CD40 partitioning into lipid rafts. FEBS-Letters 2002; 534:169–174.CrossRefGoogle Scholar
  45. 45.
    Janes PW, Ley SC, Magee AI. Aggregation of lipid rafts accompanies signaling via the T cell antigen receptor. J Cell Biol 1999; 147:447–461.PubMedCrossRefGoogle Scholar
  46. 46.
    Santana P, Pena LA, Haimovitz-Friedman A et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 1996; 86:189–199.PubMedCrossRefGoogle Scholar
  47. 47.
    Garcia-Barros M, Paris F, Cordon-Cardo C et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 2003; 300:1155–1159.PubMedCrossRefGoogle Scholar
  48. 48.
    Zhang Y, Mattjus P, Schmid PC et al. Involvement of the acid sphingomyelinase pathway in UVA-induced apoptosis. J Biol Chem 2001; 276:11775–11782.PubMedCrossRefGoogle Scholar
  49. 49.
    Chung HS, Park SR, Choi EK et al. Role of sphingomyelin-MAPKs pathway in heat-induced apoptosis. Exp Mol Med 2003; 35:181–188.PubMedGoogle Scholar
  50. 50.
    Morita Y, Perez GI, Paris F et al. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nat Med 2000; 6:1109–1114.PubMedCrossRefGoogle Scholar
  51. 51.
    Grassiné H, Gulbins E, Brenner B et al. Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells. Cell 1997; 91:605–615.CrossRefGoogle Scholar
  52. 52.
    Hauck CR, Grassmé H, Bock J et al. Acid sphingomyelinase is involved in CEACAM receptor-mediated phagocytosis of N. gonorrhoeae. FEBS-Letters 2000; 478:260–266.PubMedCrossRefGoogle Scholar
  53. 53.
    Esen M, Schreiner B, Jendrossek V et al. Mechanisms of Staphylococcus aureus induced apoptosis of human endothelial cells. Apoptosis 2001; 6:441–445.CrossRefGoogle Scholar
  54. 54.
    Jan JT, Chatterjee S, Griffin DE. Sindbis virus entry into cells triggers apoptosis by activating sphingomyelinase, leading to the release of ceramide. J Virology 2000; 74:6425–6432.PubMedCrossRefGoogle Scholar
  55. 55.
    Hanada K, Palacpac NM, Magistrado PA et al. Plasmodium falciparum phospholipase C hydrolyzing sphingomyelin and lysocholinephospholipids is a possible target for malaria chemotherapy. J Exp Med 2002; 195:23–34.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  • Volker Teichgräber
    • 1
  • Gabriele Hessler
    • 1
  • Erich Gulbins
    • 1
  1. 1.Department of Molecular BiologyUniversity of Duisberg-EssenEssenGermany

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