Abstract
Ceramide has been shown to be critically involved in multiple biological processes, for instance induction of apoptosis after ligation of death receptors or application of gamma-irradiation or UV-A light, respectively, regulation of cell differentiation, control of tumor cell growth, infection of mammalian cells with pathogenic bacteria and viruses or the control of embryo and organ development to name a few examples. Ceramide molecules form distinct large domains in the cell membrane, which may serve to re-organize cellular receptors and signalling molecules. Thus, in many conditions, ceramide may be involved in the spatial and temporal organisation of specific signalling pathways explaining the pleiotrophic effects of this lipid. Here, we focus on the role of ceramide and ceramide-enriched membrane domains, respectively, in bacterial infections, in particular of the lung, and sepsis. We describe the role of ceramide for infections with Neisseriae gonorhoeae, Staphylococcus aureus and Pseudomonas aeruginosa. Finally, we discuss newly emerging aspects of the cellular function of ceramide, i.e. its role in germ line and embryo development.
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References
Barasch, J., Kiss, B., Prince, A., Saiman, L., Gruenert, D. and al-Awqati, Q. Defective acidification of intracellular organelles in cystic fibrosis. Nature 352 (1991) 70–3.
Bock, J., Szabo, I., Gamper, N., Adams, C. Gulbins, E. Ceramide inhibits the potassium channel Kv1.3 by the formation of membrane platforms. Biochem Biophys Res Commun 305 (2003) 890–7.
Brown, D. A. London, E. Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 14 (1998) 111–36.
Butler, A., He, X., Gordon, R. E., Wu, H. S., Gatt, S. Schuchman, E. H. Reproductive pathology and sperm physiology in acid sphingomyelinase-deficient mice. Am J Pathol 161 (2002) 1061–75.
Butler, A., Gordon, R. E., Gatt, S. Schuchman, E. H. Sperm abnormalities in heterozygous acid sphingomyelinase knockout mice reveal a novel approach for the prevention of genetic diseases. Am J Pathol 170 (2007) 2077–88.
Claus, R. A., Bunck, A. C., Bockmeyer, C. L., Brunkhorst, F. M., Losche, W., Kinscherf, R. Deigner, H. P. Role of increased sphingomyelinase activity in apoptosis and organ failure of patients with severe sepsis. Faseb J 19 (2005) 1719–21.
Comiskey, M. Warner, C. M. Spatio-temporal localization of membrane lipid rafts in mouse oocytes and cleaving preimplantation embryos. Dev Biol 303 (2007) 727–39.
Cremesti, A., Paris, F., Grassme, H., Holler, N., Tschopp, J., Fuks, Z., Gulbins, E. Kolesnick, R. Ceramide enables fas to cap and kill. J Biol Chem 276 (2001) 23954–61.
Di, A., Brown, M. E., Deriy, L. V., Li, C., Szeto, F. L., Chen, Y., Huang, P., Tong, J., Naren, A. P., Bindokas, V., Palfrey, H. C. Nelson, D. J. CFTR regulates phagosome acidification in macrophages and alters bactericidal activity. Nat Cell Biol 8 (2006) 933–44.
Dumitru, C. A. Gulbins, E. TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene 25 (2006) 5612–25.
Dunkel, L., Hirvonen, V. Erkkila, K. Clinical aspects of male germ cell apoptosis during testis development and spermatogenesis. Cell Death Differ 4 (1997) 171–9.
Eliyahu, E., Park, J. H., Shtraizent, N., He, X. Schuchman, E. H. Acid ceramidase is a novel factor required for early embryo survival. Faseb J 21 (2007) 1403–9.
Emoto, K. Umeda, M. An essential role for a membrane lipid in cytokinesis. Regulation of contractile ring disassembly by redistribution of phosphatidylethanolamine. J Cell Biol 149 (2000) 1215–24.
Emoto, K., Inadome, H., Kanaho, Y., Narumiya, S. Umeda, M. Local change in phospholipid composition at the cleavage furrow is essential for completion of cytokinesis. J Biol Chem 280 (2005) 37901–7.
Eramo, A., Sargiacomo, M., Ricci-Vitiani, L., Todaro, M., Stassi, G., Messina, C. G., Parolini, I., Lotti, F., Sette, G., Peschle, C. De Maria, R. CD95 death-inducing signaling complex formation and internalization occur in lipid rafts of type I and type II cells. Eur J Immunol 34 (2004) 1930–40.
Esen, M., Schreiner, B., Jendrossek, V., Lang, F., Fassbender, K., Grassme, H. Gulbins, E. Mechanisms of Staphylococcus aureus induced apoptosis of human endothelial cells. Apoptosis 6 (2001) 431–9.
Finnegan, C. M., Rawat, S. S., Puri, A., Wang, J. M., Ruscetti, F. W. Blumenthal, R. Ceramide, a target for antiretroviral therapy. Proc Natl Acad Sci USA 101 (2004) 15452–7.
Finnegan, C. M. Blumenthal, R. Fenretinide inhibits HIV infection by promoting viral endocytosis. Antiviral Res 69 (2006) 116–23.
Göggel, R., Winoto-Morbach, S., Vielhaber, G., Imai, Y., Lindner, K., Brade, L., Brade, H., Ehlers, S., Slutsky, A. S., Schutze, S., Gulbins, E. Uhlig, S. PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide. Nat Med 10 (2004) 155–60.
Grassme, H., Gulbins, E., Brenner, B., Ferlinz, K., Sandhoff, K., Harzer, K., Lang, F. Meyer, T. F. Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells. Cell 91 (1997) 605–15.
Grassme, H., Kirschnek, S., Riethmueller, J., Riehle, A., von Kürthy, G., Lang, F., Weller, M. Gulbins, E. Host defense to Pseudomonas aeruginosa requires CD95/CD95 ligand interaction on epithelial cells. Science 290 (2000) 527–30.
Grassme, H., Schwarz, H. Gulbins, E. Molecular mechanisms of ceramide-mediated CD95 clustering. Biochem Biophys Res Commun 284 (2001a) 1016–30.
Grassme, H., Jekle, A., Riehle, A., Schwarz, H., Berger, J., Sandhoff, K., Kolesnick, R. Gulbins, E. CD95 signaling via ceramide-rich membrane rafts. J Biol Chem 276 (2001b) 20589–96.
Grassme, H., Jendrossek, V., Bock, J., Riehle, A. Gulbins, E. Ceramide-rich membrane rafts mediate CD40 clustering. J Immunol 168 (2002) 298–307.
Grassme, H., Cremesti, A., Kolesnick, R. Gulbins, E. Ceramide-mediated clustering is required for CD95-DISC formation. Oncogene 22 (2003a) 5457–70.
Grassme, H., Jendrossek, V., Riehle, A., von Kurthy, G., Berger, J., Schwarz, H., Weller, M., Kolesnick, R. Gulbins, E. Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts. Nat Med 9 (2003b) 322–30.
Grassme, H., Riehle, A., Wilker, B. Gulbins, E. Rhinoviruses infect human epithelial cells via ceramide-enriched membrane platforms. J Biol Chem 280 (2005) 26256–62.
Gulbins, E. Kolesnick, R. Measurement of sphingomyelinase activity. Methods Enzymol 322 (2000) 382–8.
Gulbins, E. Kolesnick, R. Raft ceramide in molecular medicine. Oncogene 22 (2003) 7070–7.
Haimovitz-Friedman, A., Cordon-Cardo, C., Bayoumy, S., Garzotto, M., McLoughlin, M., Gallily, R., Edwards, C. K., 3rd, Schuchman, E. H., Fuks, Z. Kolesnick, R. Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation. J Exp Med 186 (1997) 1831–41.
Hakomori, S. Chemistry of Glycosphingolipids. In: Kanfer JN, Hakomori S, editors. Sphingolipid Biochemistry. New York and London: Plenum Press (1983) 1–165.
Hanada, K., Palacpac, N. M., Magistrado, P. A., Kurokawa, K., Rai, G., Sakata, D., Hara, T., Horii, T., Nishijima, M. Mitamura, T. Plasmodium falciparum phospholipase C hydrolyzing sphingomyelin and lysocholinephospholipids is a possible target for malaria chemotherapy. J Exp Med 195 (2002) 23–34.
Hauck, C. R., Grassme, H., Bock, J., Jendrossek, V., Ferlinz, K., Meyer, T. F. Gulbins, E. Acid sphingomyelinase is involved in CEACAM receptor-mediated phagocytosis of Neisseria gonorrhoeae. FEBS Lett 478 (2000) 260–6.
Hinkovska, V. T., Petkova, D. H. Koumanov, K. S. A neutral sphingomyelinase in spermatozoal plasma membranes. Biochem Cell Biol 65 (1987) 525–8.
Holopainen, J. M., Subramanian, M. Kinnunen, P. K. Sphingomyelinase induces lipid microdomain formation in a fluid phosphatidylcholine/sphingomyelin membrane. Biochemistry 37 (1998) 17562–70.
Jan, J. T., Chatterjee, S. Griffin, D. E. Sindbis virus entry into cells triggers apoptosis by activating sphingomyelinase, leading to the release of ceramide. J Virol 74 (2000) 6425–32.
Joseph, T., Look, D. Ferkol, T. NF-kappaB activation and sustained IL-8 gene expression in primary cultures of cystic fibrosis airway epithelial cells stimulated with Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol 288 (2005) L471–9.
Kidder, G. M. Mhawi, A. A. Gap junctions and ovarian folliculogenesis. Reproduction 123 (2002) 613–20.
Kitatani, K., Idkowiak-Baldys, J. Hannun, Y. A. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal (2007) PMID 18191382
Kolesnick, R. N., Goni, F. M. Alonso, A. Compartmentalization of ceramide signaling: physical foundations and biological effects. J Cell Physiol 184 (2000) 285–300.
Kono, M., Mi, Y., Liu, Y., Sasaki, T., Allende, M. L., Wu, Y. P., Yamashita, T. Proia, R. L. The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J Biol Chem 279 (2004) 29367–73.
Krishnamurthy, K., Wang, G., Silva, J., Condie, B. G. Bieberich, E. Ceramide regulates atypical PKCzeta/lambda-mediated cell polarity in primitive ectoderm cells. A novel function of sphingolipids in morphogenesis. J Biol Chem 282 (2007) 3379–90.
Lang, P. A., Schenck, M., Nicolay, J. P., Becker, J. U., Kempe, D. S., Lupescu, A., Koka, S., Eisele, K., Klarl, B. A., Rubben, H., Schmid, K. W., Mann, K., Hildenbrand, S., Hefter, H., Huber, S. M., Wieder, T., Erhardt, A., Häussinger, D., Gulbins, E. Lang, F. Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat Med 13 (2007) 164–70.
Lee, J., Richburg, J. H., Younkin, S. C. Boekelheide, K. The Fas system is a key regulator of germ cell apoptosis in the testis. Endocrinology 138 (1997) 2081–8.
Li, C. M., Park, J. H., Simonaro, C. M., He, X., Gordon, R. E., Friedman, A. H., Ehleiter, D., Paris, F., Manova, K., Hepbildikler, S., Fuks, Z., Sandhoff, K., Kolesnick, R. Schuchman, E. H. Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes. Genomics 79 (2002) 218–24.
Lindner, K., Uhlig, U. Uhlig, S. Ceramide alters endothelial cell permeability by a nonapoptotic mechanism. Br J Pharmacol 145 (2005) 132–40.
London, M. London, E. Ceramide selectively displaces cholesterol from ordered lipid domains (rafts): implications for lipid raft structure and function. J Biol Chem 279 (2004) 9997–10004.
London, M., Bakht, O. London, E. Cholesterol precursors stabilize ordinary and ceramide-rich ordered lipid domains (lipid rafts) to different degrees. Implications for the Bloch hypothesis and sterol biosynthesis disorders. J Biol Chem 281 (2006) 21903–13.
Mizugishi, K., Yamashita, T., Olivera, A., Miller, G. F., Spiegel, S. Proia, R. L. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 25 (2005) 11113–21.
Mizugishi, K., Li, C., Olivera, A., Bielawski, J., Bielawska, A., Deng, C. X. Proia, R. L. Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice. J Clin Invest 117 (2007) 2993–3006.
Morita, Y., Perez, G. I., Paris, F., Miranda, S. R., Ehleiter, D., Haimovitz-Friedman, A., Fuks, Z., Xie, Z., Reed, J. C., Schuchman, E. H., Kolesnick, R. N. Tilly, J. L. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nat Med 6 (2000) 1109–14.
Nurminen, T. A., Holopainen, J. M., Zhao, H. Kinnunen, P. K. Observation of topical catalysis by sphingomyelinase coupled to microspheres. J Am Chem Soc 124 (2002) 12129–34.
Otala, M., Pentikainen, M. O., Matikainen, T., Suomalainen, L., Hakala, J. K., Perez, G. I., Tenhunen, M., Erkkila, K., Kovanen, P., Parvinen, M. Dunkel, L. Effects of acid sphingomyelinase deficiency on male germ cell development and programmed cell death. Biol Reprod 72 (2005) 86–96.
Perez, G. I., Jurisicova, A., Matikainen, T., Moriyama, T., Kim, M. R., Takai, Y., Pru, J. K., Kolesnick, R. N. Tilly, J. L. A central role for ceramide in the age-related acceleration of apoptosis in the female germline. Faseb J 19 (2005) 860–2.
Pier, G. B., Grout, M., Zaidi, T. S., Olsen, J. C., Johnson, L. G., Yankaskas, J. R. Goldberg, J. B. Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science 271 (1996) 64–7.
Print, C. G. Loveland, K. L. Germ cell suicide: new insights into apoptosis during spermatogenesis. Bioessays 22 (2000) 423–30.
Quintern, L. E., Schuchman, E. H., Levran, O., Suchi, M., Ferlinz, K., Reinke, H., Sandhoff, K. Desnick, R. J. Isolation of cDNA clones encoding human acid sphingomyelinase: occurrence of alternatively processed transcripts. Embo J 8 (1989) 2469–73.
Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J. L. and et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245 (1989) 1066–73.
Rossant, J. Lineage development and polar asymmetries in the peri-implantation mouse blastocyst. Semin Cell Dev Biol 15 (2004) 573–81.
Schissel, S. L., Schuchman, E. H., Williams, K. J. Tabas, I. Zn2+-stimulated sphingomyelinase is secreted by many cell types and is a product of the acid sphingomyelinase gene. J Biol Chem 271 (1996) 18431–6.
Schissel, S. L., Keesler, G. A., Schuchman, E. H., Williams, K. J. Tabas, I. The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene. J Biol Chem 273 (1998) 18250–9.
Simons, K. Ikonen, E. Functional rafts in cell membranes. Nature 387 (1997) 569–72.
Singer, S. J. Nicolson, G. L. The fluid mosaic model of the structure of cell membranes. Science 175 (1972) 720–31.
Spence, M. W., Burgess, J. K. Sperker, E. R. Neutral and acid sphingomyelinases: somatotopographical distribution in human brain and distribution in rat organs. A possible relationship with the dopamine system. Brain Res 168 (1979) 543–51.
Teichgräber, V., Ulrich, M., Endlich, N., Riethmüller, J., Wilker, B., De Oliveira-Munding, C., van Heeckeren, A. M., Barr, M. L., von Kurthy, G., Schmid, K. W., Weller, M., Tümmler, B., Lang, F., Grassme, H., Döring, G. Gulbins, E. Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat Med (2008) in Press.
ten Grotenhuis, E., Demel, R. A., Ponec, M., Boer, D. R., van Miltenburg, J. C. Bouwstra, J. A. Phase behavior of stratum corneum lipids in mixed Langmuir-Blodgett monolayers. Biophys J 71 (1996) 1389–99.
Trajkovic, K., Hsu, C., Chiantia, S., Rajendran, L., Wenzel, D., Wieland, F., Schwille, P., Brugger, B. Simons, M. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319 (2008) 1244–7.
Veiga, M. P., Arrondo, J. L., Goni, F. M. Alonso, A. Ceramides in phospholipid membranes: effects on bilayer stability and transition to nonlamellar phases. Biophys J 76 (1999) 342–50.
von Bismarck, P., Garcia Wistadt, C. F., Klemm, K., Winoto-Morbach, S., Uhlig, U., Schutze, S., Adam, D., Lachmann, B., Uhlig, S. Krause, M. F. Improved pulmonary function by acid sphingomyelinase inhibition in a newborn piglet lavage model. Am J Respir Crit Care Med (2008) PMID 18310483.
Wu, J., Zhang, L. Wang, X. Maturation and apoptosis of human oocytes in vitro are age-related. Fertil Steril 74 (2000) 1137–41.
Xu, X., Bittman, R., Duportail, G., Heissler, D., Vilcheze, C. London, E. Effect of the structure of natural sterols and sphingolipids on the formation of ordered sphingolipid/sterol domains (rafts). Comparison of cholesterol to plant, fungal, and disease-associated sterols and comparison of sphingomyelin, cerebrosides, and ceramide. J Biol Chem 276 (2001) 33540–6.
Yamashita, T., Wada, R., Sasaki, T., Deng, C., Bierfreund, U., Sandhoff, K. Proia, R. L. A vital role for glycosphingolipid synthesis during development and differentiation. Proc Natl Acad Sci USA 96 (1999) 9142–7.
Zahm, J. M., Gaillard, D., Dupuit, F., Hinnrasky, J., Porteous, D., Dorin, J. R. Puchelle, E. Early alterations in airway mucociliary clearance and inflammation of the lamina propria in CF mice. Am J Physiol 272 (1997) C853–9.
Zhang, D. X., Zou, A. P. Li, P. L. Ceramide reduces endothelium-dependent vasodilation by increasing superoxide production in small bovine coronary arteries. Circ Res 88 (2001) 824–31.
Zhang, D. X., Zou, A. P. Li, P. L. Ceramide-induced activation of NADPH oxidase and endothelial dysfunction in small coronary arteries. Am J Physiol Heart Circ Physiol 284 (2003) H605–12.
Acknowledgements
Parts of the work described in the present review was supported by German Research Foundation grants DFG 774/21-2 and DFG 774/22-1 to E.W. and DFG 335/16-1 to E.G.
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Becker, K.A., Gellhaus, A., Winterhager, E., Gulbins, E. (2008). Ceramide-Enriched Membrane Domains in Infectious Biology and Development. In: Quinn, P.J., Wang, X. (eds) Lipids in Health and Disease. Subcellular Biochemistry, vol 49. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-8831-5_20
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