Skip to main content
SpringerLink
Log in

Glycosphingolipids and cell death: one aim, many ways

  • THE ROLE OF SPHINGOLIPIDS AND LIPID RAFTS IN DETERMINING CELL FATE
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Glycosphingolipids (GSLs) are a family of bioactive lipids that in addition to their role in the regulation of structural properties of membrane bilayers have emerged as crucial players in many biological processes and signal transduction pathways. Rather than being uniformly distributed within membrane bilayers, GSLs are localized in selective domains called lipid rafts where many signaling platforms operate. One of the most important functions of GSLs, particularly ceramide, is their ability to regulate cell death pathways and hence cell fate. This complex role is accomplished by the ability of GSLs to act in distinct subcellular strategic centers, such as mitochondria, endoplasmic reticulum (ER) or lysosomes to mediate apoptosis, ER stress, autophagy, lysosomal membrane permeabilization and necroptosis. Hence better understanding the role of GSLs in cell death may be of relevance for a number of pathological processes and diseases, including neurodegeneration, metabolic liver diseases and cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139–150

    CAS  PubMed  Google Scholar 

  2. Ogretmen B, Hannun YA (2004) Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 4:604–616

    CAS  PubMed  Google Scholar 

  3. Chavez JA, Summers SA (2012) A ceramide-centric view of insulin resistance. Cell Metab 15:585–594

    CAS  PubMed  Google Scholar 

  4. Maceyka M, Spiegel S (2014) Sphingolipid metabolites in inflammatory disease. Nature 510:58–67

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Morales A, Lee H, Goñi F, Kolesnick R, Fernandez-Checa J (2007) Sphingolipids and cell death. Apoptosis 12:923–939

    CAS  PubMed  Google Scholar 

  6. Mizutani Y, Kihara A, Chiba H, Tojo H, Igarashi Y (2008) 2-Hydroxy-ceramide synthesis by ceramide synthase family: enzymatic basis for the preference of FA chain length. J Lipid Res 49:2356–2364

    CAS  PubMed  Google Scholar 

  7. Park JW, Park WJ, Futerman AH (1841) Ceramide synthases as potential targets for therapeutic intervention in human diseases. Biochim Biophys Acta 671–681:2014

    Google Scholar 

  8. Grösch S, Schiffmann S, Geisslinger G (2012) Chain length-specific properties of ceramides. Prog Lipid Res 51:50–62

    PubMed  Google Scholar 

  9. Pewzner-Jung Y, Brenner O, Braun S, Laviad EL, Ben-Dor S, Feldmesser E, Horn-Saban S, Amann-Zalcenstein D, Raanan C, Berkutzki T, Erez-Roman R, Ben-David O, Levy M, Holzman D, Park H, Nyska A, Merrill AH Jr, Futerman AH (2010) A critical role for ceramide synthase 2 in liver homeostasis: II. Insights into molecular changes leading to hepatopathy. J Biol Chem 285:10911–10923

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Turpin SM, Nicholls HT, Willmes DM, Mourier A, Brodesser S, Wunderlich CM, Mauer J, Xu E, Hammerschmidt P, Brönneke HS, Trifunovic A, LoSasso G, Wunderlich FT, Kornfeld JW, Blüher M, Krönke M, Brüning JC (2014) Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab 20:678–686

    CAS  PubMed  Google Scholar 

  11. Raichur S, Wang ST, Chan PW, Li Y, Ching J, Chaurasia B, Dogra S, Öhman MK, Takeda K, Sugii S, Pewzner-Jung Y, Futerman AH, Summers SA (2014) CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab 20:687–695

    CAS  PubMed  Google Scholar 

  12. Bartke N, Hannun YA (2009) Bioactive sphingolipids: metabolism and function. J Lipid Res 50:S91–S96

    PubMed Central  PubMed  Google Scholar 

  13. Breslow DK, Weissman JS (2010) Membranes in balance: mechanisms of sphingolipid homeostasis. Mol Cell 40:267–279

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Bikman BT, Summers SA (2011) Ceramides as modulators of cellular and whole-body metabolism. J Clin Invest 121:4222–4230

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Holland WL, Summers SA (2008) Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev 29:381–402

    PubMed Central  CAS  PubMed  Google Scholar 

  16. Paumen MB, Ishida Y, Muramatsu M, Yamamoto M, Honjo T (1997) Inhibition of carnitine palmitoyltransferase i augments sphingolipid synthesis and palmitate-induced apoptosis. J Biol Chem 272:3324–3329

    CAS  PubMed  Google Scholar 

  17. Straczkowski M, Kowalska I, Baranowski M, Nikolajuk A, Otziomek E, Zabielski P, Adamska A, Blachnio A, Gorski J, Gorska M (2007) Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes. Diabetologia 50:2366–2373

    CAS  PubMed  Google Scholar 

  18. Watt MJ, Barnett AC, Bruce CR, Schenk S, Horowitz JF, Hoy AJ (2012) Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide. Diabetologia 55:2741–2746

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Breslow DK, Collins SR, Bodenmiller B, Aebersold R, Simons K, Shevchenko A, Ejsing CS, Weissman JS (2010) Orm family proteins mediate sphingolipid homeostasis. Nature 463:1048–1053

    PubMed Central  CAS  PubMed  Google Scholar 

  20. Roelants FM, Breslow DK, Muir A, Weissman JS, Thorner J (2011) Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae. Proc Natl Acad Sci 108:19222–19227

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Aronova S, Wedaman K, Aronov PA, Fontes K, Ramos K, Hammock BD, Powers T (2008) Regulation of ceramide biosynthesis by TOR complex 2. Cell Metab 7:148–158

    CAS  PubMed  Google Scholar 

  22. Dickson RC (2008) Thematic review series: sphingolipids. New insights into sphingolipid metabolism and function in budding yeast. J Lipid Res 49:909–921

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Berchtold D, Piccolis M, Chiaruttini N, Riezman I, Riezman H, Roux A, Walther TC, Loewith R (2012) Plasma membrane stress induces relocalization of Slm proteins and activation of TORC2 to promote sphingolipid synthesis. Nat Cell Biol 14:542–547

    CAS  PubMed  Google Scholar 

  24. Siow DL, Wattenberg BW (2012) Mammalian ORMDL proteins mediate the feedback response in ceramide biosynthesis. J Biol Chem 287:40198–40204

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Gupta SD, Gable K, Alexaki A, Chandris P, Proia RL, Dunn TM, Harmon JM (2014) Expression of the ORMDLS, modulators of serine palmitoyltransferase, is regulated by sphingolipids in mammalian cells. J Biol Chem. doi:10.1074/jbc.M114.588236

    Google Scholar 

  26. Canals D, Perry DM, Jenkins RW, Hannun YA (2011) Drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidases. Br J Pharmacol 163:694–712

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Smith EL, Schuchman EH (2008) The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases. FASEB J 22:3419–3431

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Angulo S, Morales A, Danese S, Llacuna L, Masamunt MC, Pultz N, Cifone MG, De Simone C, Delgado S, Vila J, Panes J, Donskey C, Fernandez-Checa JC, Fiocchi C, Sans M (2011) Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase. PLoS One 6:e16953

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Coll O, Morales A, Fernández-Checa JC, Garcia-Ruiz C (2007) Neutral sphingomyelinase-induced ceramide triggers germinal vesicle breakdown and oxidant-dependent apoptosis in Xenopus laevis oocytes. J Lipid Res 48:1924–1935

    CAS  PubMed  Google Scholar 

  30. Marí M, Fernández-Checa JC (2007) Sphingolipid signalling and liver diseases. Liver Int 27:440–450

    PubMed  Google Scholar 

  31. Garcia-Ruiz C, Colell A, Mari M, Morales A, Calvo M, Enrich C, Fernandez-Checa JC (2003) Defective TNF-α-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J Clin Invest 111:197–208

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Mari M, Colell A, Morales A, Paneda C, Varela-Nieto I, Garcia-Ruiz C, Fernandez-Checa JC (2004) Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis. J Clin Invest 113:895–904

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Lin T, Genestier L, Pinkoski MJ, Castro A, Nicholas S, Mogil R, Paris F, Fuks Z, Schuchman EH, Kolesnick RN, Green DR (2000) Role of acidic sphingomyelinase in Fas/CD95-mediated cell death. J Biol Chem 275:8657–8663

    CAS  PubMed  Google Scholar 

  34. Lang PA, Schenck M, Nicolay JP, Becker JU, Kempe DS, Lupescu A, Koka S, Eisele K, Klarl BA, Rubben H, Schmid KW, Mann K, Hildenbrand S, Hefter H, Huber SM, Wieder T, Erhardt A, Haussinger D, Gulbins E, Lang F (2007) Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat Med 13:164–170

    CAS  PubMed  Google Scholar 

  35. Fucho R, Martinez L, Baulies A, Torres S, Tarrats N, Fernandez A, Ribas V, Astudillo AM, Balsinde J, Garcia-Roves P, Elena M, Bergheim I, Lotersztajn S, Trautwein C, Appelqvist H, Paton AW, Paton JC, Czaja MJ, Kaplowitz N, Fernandez-Checa JC, Garcia-Ruiz C (2014) Asmase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage nonalcoholic steatohepatitis. J Hepatol. doi:10.1016/j.jhep.2014.06.009

    PubMed  Google Scholar 

  36. Fernandez A, Matias N, Fucho R, Ribas V, Von Montfort C, Nuño N, Baulies A, Martinez L, Tarrats N, Mari M, Colell A, Morales A, Dubuquoy L, Mathurin P, Bataller R, Caballeria J, Elena M, Balsinde J, Kaplowitz N, Garcia-Ruiz C, Fernandez-Checa JC (2013) ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading. J Hepatol 59:805–813

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Jenkins RW, Idkowiak-Baldys J, Simbari F, Canals D, Roddy P, Riner CD, Clarke CJ, Hannun YA (2011) A novel mechanism of lysosomal acid sphingomyelinase maturation: requirement for carboxyl-terminal proteolytic processing. J Biol Chem 286:3777–3788

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Paris F, Grassmé H, Cremesti A, Zager J, Fong Y, Haimovitz-Friedman A, Fuks Z, Gulbins E, Kolesnick R (2001) Natural ceramide reverses fas resistance of acid sphingomyelinase(−/−) hepatocytes. J Biol Chem 276:8297–8305

    CAS  PubMed  Google Scholar 

  39. Llacuna L, Mari M, Garcia-Ruiz C, Fernandez-Checa JC, Morales A (2006) Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. Hepatology (Hoboken, NJ, U. S.) 44:561–572

    CAS  Google Scholar 

  40. Grassme H, Jekle A, Riehle A, Schwarz H, Berger J, Sandhoff K, Kolesnick R, Gulbins E (2001) CD95 signaling via ceramide-rich membrane rafts. J Biol Chem 276:20589–20596

    CAS  PubMed  Google Scholar 

  41. Cremesti A, Paris F, Grassmé H, Holler N, Tschopp J, Fuks Z, Gulbins E, Kolesnick R (2001) Ceramide enables fas to cap and kill. J Biol Chem 276:23954–23961

    CAS  PubMed  Google Scholar 

  42. Grassmé H, Cremesti A, Kolesnick R, Gulbins E (2003) Ceramide-mediated clustering is required for CD95-DISC formation. Oncogene 22:5457–5470

    Google Scholar 

  43. Perrotta C, Bizzozero L, Cazzato D, Morlacchi S, Assi E, Simbari F, Zhang Y, Gulbins E, Bassi MT, Rosa P, Clementi E (2010) Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function. J Biol Chem 285:40240–40251

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E, Matteoli M, Verderio C (2009) Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J 28:1043–1054

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Ridgway ND (2000) Interactions between metabolism and intracellular distribution of cholesterol and sphingomyelin. Biochimica et Biophysica Acta (BBA) - Mol Cell Biol Lipids 1484:129–141

    CAS  Google Scholar 

  46. Slotte JP (1999) Sphingomyelin–cholesterol interactions in biological and model membranes. Chem Phys Lipids 102:13–27

    CAS  PubMed  Google Scholar 

  47. Li X, Xu M, Pitzer A, Xia M, Boini K, Li P-L, Zhang Y (2014) Control of autophagy maturation by acid sphingomyelinase in mouse coronary arterial smooth muscle cells: protective role in atherosclerosis. J Mol Med 92:473–485

    CAS  PubMed  Google Scholar 

  48. Alayoubi AM, Wang JC, Au BC, Carpentier S, Garcia V, Dworski S, El-Ghamrasni S, Kirouac KN, Exertier MJ, Xiong ZJ, Privé GG, Simonaro CM, Casas J, Fabrias G, Schuchman EH, Turner PV, Hakem R, Levade T, Medin JA (2013) Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO Mol Med 5:827–842

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Chipuk JE, Mcstay GP, Bharti A, Kuwana T, Clarke CJ, Siskind LJ, Obeid LM, Green (2012) Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell 148:988–1000

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Lee SH, Seo GS, Park P-H, Choi J-Y, Park YN, Kim HK, Chae K-S, Sohn DH (2003) Increased expression of O-acetyl disialoganglioside synthase during rat liver fibrogenesis relates to stellate cell activation. Biochem Biophys Res Commun 303:954–961

    CAS  PubMed  Google Scholar 

  51. Huitema K, Van Den Dikkenberg J, Brouwers JFHM, Holthuis JCM (2004) Identification of a family of animal sphingomyelin synthases. EMBO J 23:33–44

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Vacaru AM, Tafesse FG, Ternes P, Kondylis V, Hermansson M, Brouwers JFHM, Somerharju P, Rabouille C, Holthuis JCM (2009) Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER. J Cell Biol 185:1013–1027

    PubMed Central  CAS  PubMed  Google Scholar 

  53. D’angelo G, Polishchuk E, Tullio GD, Santoro M, Campli AD, Godi A, West G, Bielawski J, Chuang C-C, Van Der Spoel AC, Platt FM, Hannun YA, Polishchuk R, Mattjus P, De Matteis MA (2007) Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 449:62–67

    PubMed  Google Scholar 

  54. Mao C, Obeid LM (2008) Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochimica et Biophysica Acta (BBA) - Mol Cell Biol Lipids 1781:424–434

    CAS  Google Scholar 

  55. Hassler DF, Bell RM (1993) Ceramidases: enzymology and metabolic roles. Adv Lipid Res 26:49–57

    CAS  PubMed  Google Scholar 

  56. Franzen R, Pautz A, Bräutigam L, Geisslinger G, Pfeilschifter J, Huwiler A (2001) Interleukin-1β induces chronic activation and de novo synthesis of neutral ceramidase in renal mesangial cells. J Biol Chem 276:35382–35389

    CAS  PubMed  Google Scholar 

  57. Ramirez De Molina A, De La Cueva A, Machado-Pinilla R, Rodriguez-Fanjul V, Gomez Del Pulgar T, Cebrian A, Perona R, Lacal JC (2012) Acid ceramidase as a chemotherapeutic target to overcome resistance to the antitumoral effect of choline kinase α inhibition. Curr Cancer Drug Targets 12:617–624

    CAS  PubMed  Google Scholar 

  58. Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind JS, Spiegel S (1996) Suppression of ceramide-mediated programmed cell death. Nature 381:800–803

    CAS  PubMed  Google Scholar 

  59. Pyne NJ, Pyne S (2010) Sphingosine 1-phosphate and cancer. Nat Rev Cancer 10:489–503

    CAS  PubMed  Google Scholar 

  60. Perez GI, Knudson CM, Leykin L, Korsmeyer SJ, Tilly JL (1997) Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction. Nat Med 3:1228–1232

    CAS  PubMed  Google Scholar 

  61. Visentin B, Vekich JA, Sibbald BJ, Cavalli AL, Moreno KM, Matteo RG, Garland WA, Lu Y, Yu S, Hall HS, Kundra V, Mills GB, Sabbadini RA (2006) Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9:225–238

    CAS  PubMed  Google Scholar 

  62. Cingolani F, Casasampere M, Sanllehi P, Casas J, Bujons J, Fabrias G (2014) Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II. J Lipid Res 55:1711–1720

    CAS  PubMed  Google Scholar 

  63. Van Veldhoven PP (2000) Sphingosine-1-phosphate lyase. Methods Enzymol 311:244–254

    PubMed  Google Scholar 

  64. Le Stunff H, Giussani P, Maceyka M, Lépine S, Milstien S, Spiegel S (2007) Recycling of sphingosine is regulated by the concerted actions of sphingosine-1-phosphate phosphohydrolase 1 and sphingosine kinase 2. J Biol Chem 282:34372–34380

    PubMed  Google Scholar 

  65. Liu H, Sugiura M, Nava VE, Edsall LC, Kono K, Poulton S, Milstien S, Kohama T, Spiegel S (2000) Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem 275:19513–19520

    CAS  PubMed  Google Scholar 

  66. Spiegel S, Milstien S (2003) Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4:397–407

    CAS  PubMed  Google Scholar 

  67. Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241

    CAS  PubMed  Google Scholar 

  68. García-Ruiz C, Colell A, Marí M, Morales A, Fernández-Checa JC (1997) Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species: role of mitochondrial glutathione. J Biol Chem 272:11369–11377

    PubMed  Google Scholar 

  69. Gudz TI, Tserng K-Y, Hoppel CL (1997) direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem 272:24154–24158

    CAS  PubMed  Google Scholar 

  70. Dai Q, Liu J, Chen J, Durrant D, Mcintyre TM, Lee RM (2004) Mitochondrial ceramide increases in UV-irradiated HeLa cells and is mainly derived from hydrolysis of sphingomyelin. Oncogene 23:3650–3658

    CAS  PubMed  Google Scholar 

  71. Birbes H, Luberto C, Hsu Y-T, El Bawab S, Hannun YA, Obeid LM (2005) A mitochondrial pool of sphingomyelin is involved in TNFalpha-induced Bax translocation to mitochondria. Biochem J 386:445–451

    PubMed Central  CAS  PubMed  Google Scholar 

  72. El Bawab S, Roddy P, Qian T, Bielawska A, Lemasters JJ, Hannun YA (2000) Molecular cloning and characterization of a human mitochondrial ceramidase. J Biol Chem 275:21508–21513

    PubMed  Google Scholar 

  73. Bionda C, Portoukalian J, Schmitt D, Rodriguez-Lafrasse C, Ardail D (2004) Subcellular compartmentalization of ceramide metabolism: MAM (mitochondria-associated membrane) and/or mitochondria? Biochem J 382:527–533

    PubMed Central  CAS  PubMed  Google Scholar 

  74. De Maria R, Rippo MR, Schuchman EH, Testi R (1998) Acidic sphingomyelinase (ASM) is necessary for Fas-induced GD3 ganglioside-accumulation and efficient apoptosis of lymphoid cells. J Exp Med 187:897–902

    PubMed Central  PubMed  Google Scholar 

  75. García-Ruiz C, Colell A, París R, Fernández-Checa JC (2000) Direct interaction of GD3 ganglioside with mitochondria generates reactive oxygen species followed by mitochondrial permeability transition, cytochrome c release, and caspase activation. FASEB J 14:847–858

    PubMed  Google Scholar 

  76. Kristal BS, Brown AM (1999) Apoptogenic ganglioside GD3 directly induces the mitochondrial permeability transition. J Biol Chem 274:23169–23175

    CAS  PubMed  Google Scholar 

  77. Rippo MR, Malisan F, Ravagnan L, Tomassini B, Condo I, Costantini P, Susin SA, Rufini A, Todaro M, Kroemer G, Testi R (2000) GD3 ganglioside directly targets mitochondria in a bcl-2-controlled fashion. FASEB J 14:2047–2054

    CAS  PubMed  Google Scholar 

  78. García-Ruiz C, Colell A, Morales A, Calvo MA, Enrich C, Fernández-Checa JC (2002) Trafficking of ganglioside GD3 to mitochondria by tumor necrosis factor-α. J Biol Chem 277:36443–36448

    PubMed  Google Scholar 

  79. Brenner C, Kniep B, Maillier E, Martel C, Franke C, Röber N, Bachmann M, Rieber EP, Sandhoff R (2010) GD3–7-aldehyde is an apoptosis inducer and interacts with adenine nucleotide translocase. Biochem Biophys Res Commun 391:248–253

    CAS  PubMed  Google Scholar 

  80. Sorice M, Mattei V, Matarrese P, Garofalo T, Tinari A, Gambardella L, Ciarlo L, Manganelli V, Tasciotti V, Misasi R, Malorni W (2012) Dynamics of mitochondrial raft-like microdomains in cell life and death. Commun Integr Biol 5:217–219

    PubMed Central  CAS  PubMed  Google Scholar 

  81. Lee H, Rotolo JA, Mesicek J, Penate-Medina T, Rimner A, Liao W-C, Yin X, Ragupathi G, Ehleiter D, Gulbins E, Zhai D, Reed JC, Haimovitz-Friedman A, Fuks Z, Kolesnick R (2011) Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. PLoS One 6:e19783

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Ciarlo L, Manganelli V, Garofalo T, Matarrese P, Tinari A, Misasi R, Malorni W, Sorice M (2010) Association of fission proteins with mitochondrial raft-like domains. Cell Death Differ 17:1047–1058

    CAS  PubMed  Google Scholar 

  83. Galluzzi L, Bravo-San Pedro JM, Kroemer G (2014) Organelle-specific initiation of cell death. Nat Cell Biol 16:728–736

    CAS  PubMed  Google Scholar 

  84. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633

    CAS  PubMed  Google Scholar 

  85. Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC (2003) Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22:8608–8618

    CAS  PubMed  Google Scholar 

  86. Lloyd-Evans E, Pelled D, Riebeling C, Bodennec J, De-Morgan A, Waller H, Schiffmann R, Futerman AH (2003) Glucosylceramide and glucosylsphingosine modulate calcium mobilization from brain microsomes via different mechanisms. J Biol Chem 278:23594–23599

    CAS  PubMed  Google Scholar 

  87. Pelled D, Lloyd-Evans E, Riebeling C, Jeyakumar M, Platt FM, Futerman AH (2003) Inhibition of calcium uptake via the sarco/endoplasmic reticulum Ca2+-atpase in a mouse model of sandhoff disease and prevention by treatment with N-butyldeoxynojirimycin. J Biol Chem 278:29496–29501

    CAS  PubMed  Google Scholar 

  88. Tessitore A, Del P Martin M, Sano R, Ma Y, Mann L, Ingrassia A, Laywell ED, Steindler DA, Hendershot LM, D’azzo A (2004) GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol Cell 15:753–766

    CAS  PubMed  Google Scholar 

  89. Carracedo A, Lorente M, Egia A, Blázquez C, García S, Giroux V, Malicet C, Villuendas R, Gironella M, González-Feria L, Piris MÁ, Iovanna JL, Guzmán M, Velasco G (2006) The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell 9:301–312

    CAS  PubMed  Google Scholar 

  90. Boslem E, Weir JM, Macintosh G, Sue N, Cantley J, Meikie PJ, Biden TJ (2013) Alteration of endoplasmic reticulum lipid rafts contributes to lipotoxicity in pancreatic β-cells. J Biol Chem 288:26569–26582

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Gozuacik D, Kimchi A (2007) Autophagy and cell death. Curr Top Dev Biol 78:217–245

    CAS  PubMed  Google Scholar 

  92. Yu L, Wan F, Dutta S, Welsh S, Liu Z, Freundt E, Baehrecke EH, Lenardo M (2006) Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci USA 103:4952–4957

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Li Y, Li S, Qin X, Hou W, Dong H, Yao L, Xiong L (2014) The pleiotropic roles of sphingolipid signaling in autophagy. Cell Death Dis 5:e1245

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Schubert KM, Scheid MP, Duronio V (2000) Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473. J Biol Chem 275:13330–13335

    CAS  PubMed  Google Scholar 

  95. Edinger AL (2009) Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analyzing nutrient transporter expression. Biochem Soc Trans 37:253–258

    CAS  PubMed  Google Scholar 

  96. Guenther GG, Peralta ER, Rosales KR, Wong SY, Siskind LJ, Edinger AL (2008) Ceramide starves cells to death by downregulating nutrient transporter proteins. Proc Natl Acad Sci USA. 105:17402–17407

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Scarlatti F, Bauvy C, Ventruti A, Sala G, Cluzeaud F, Vandewalle A, Ghidoni R, Codogno P (2004) Ceramide-mediated Macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J Biol Chem 279:18384–18391

    CAS  PubMed  Google Scholar 

  98. Young MM, Kester M, Wang H-G (2013) Sphingolipids: regulators of crosstalk between apoptosis and autophagy. J Lipid Res 54:5–19

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Spassieva SD, Mullen TD, Townsend DM, Obeid LM (2009) Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response. Biochem J 424:273–283

    CAS  PubMed  Google Scholar 

  100. Russo SB, Baicu CF, Van Laer A, Geng T, Kasiganesan H, Zile MR, Cowart LA (2012) Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J Clin Invest 122:3919–3930

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Beauchamp E, Goenaga D, Le Bloch J, Catheline D, Legrand P, Rioux V (2007) Myristic acid increases the activity of dihydroceramide Delta4-desaturase 1 through its N-terminal myristoylation. Biochimie 89:1553–1561

    CAS  PubMed  Google Scholar 

  102. Jiang W, Ogretmen B (2014) Autophagy paradox and ceramide. Biochimica et Biophysica Acta (BBA) - Mol Cell Biol Lipids 1841:783–792

    CAS  Google Scholar 

  103. Park MA, Zhang G, Martin AP, Hamed H, Mitchell C, Hylemon PB, Graf M, Rahmani M, Ryan K, Liu X, Spiegel S, Norris J, Fisher PB, Grant S, Dent P (2008) Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation. Cancer Biol Ther 7:1648–1662

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Li DD, Wang LL, Deng R, Tang J, Shen Y, Guo JF, Wang Y, Xia LP, Feng GK, Liu QQ, Huang WL, Zeng YX, Zhu XF (2009) The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells. Oncogene 28:886–898

    CAS  PubMed  Google Scholar 

  105. Zeidan YH, Jenkins RW, Hannun YA (2008) Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathway. J Cell Biol 181:335–350

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Matarrese P, Garofalo T, Manganelli V, Gambardella L, Marconi M, Grasso M, Tinari A, Misasi R, Malorni W, Sorice M (2014) Evidence for the involvement of GD3 ganglioside in autophagosome formation and maturation. Autophagy 10:750–765

    CAS  PubMed  Google Scholar 

  107. Hwang J, Lee S, Lee JT, Kwon TK, Kim DR, Kim H, Park HC, Suk K (2010) Gangliosides induce autophagic cell death in astrocytes. Br J Pharmacol 159:586–603

    PubMed Central  CAS  PubMed  Google Scholar 

  108. Li ZZ, Berk M, Mcintyre TM, Gores GJ, Feldstein AE (2008) The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity. Hepatology (Hoboken, NJ, U. S.) 47:1495–1503

    CAS  Google Scholar 

  109. Petersen NHT, Olsen OD, Groth-Pedersen L, Ellegaard A-M, Bilgin M, Redmer S, Ostenfeld MS, Ulanet D, Dovmark TH, Lønborg A, Vindeløv SD, Hanahan D, Arenz C, Ejsing CS, Kirkegaard T, Rohde M, Nylandsted J, Jäättelä M (2013) Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase. Cancer Cell 24:379–393

    CAS  PubMed  Google Scholar 

  110. Appelqvist H, Nilsson C, Garner B, Brown AJ, Kågedal K, Öllinger K (2011) Attenuation of the lysosomal death pathway by lysosomal cholesterol accumulation. Am J Pathol 178:629–639

    PubMed Central  CAS  PubMed  Google Scholar 

  111. Ullio C, Casas J, Brunk UT, Sala G, Fabriàs G, Ghidoni R, Bonelli G, Baccino FM, Autelli R (2012) Sphingosine mediates TNFα-induced lysosomal membrane permeabilization and ensuing programmed cell death in hepatoma cells. J Lipid Res 53:1134–1143

    PubMed Central  CAS  PubMed  Google Scholar 

  112. Villamil Giraldo AM, Appelqvist H, Ederth T, Öllinger K (2014) Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death. Biochem Soc Trans 42:1460–1464

    CAS  PubMed  Google Scholar 

  113. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D (1995) Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376:167–170

    CAS  PubMed  Google Scholar 

  114. Doi TS, Takahshi T, Taguchi O, Azuma T, Obata Y (1997) NF-kappa B RelA-deficient lymphocytes: normal development of T cells and B cells, impaired production of IgA and IgG1 and reduced proliferative responses. J Exp Med 185:953–961

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Schütze S, Potthoff K, Machleidt T, Berkovic D, Wiegmann K, Krönke M (1992) TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 71:765–776

    PubMed  Google Scholar 

  116. Dbaibo GS, Obeid LM, Hannun YA (1993) Tumor necrosis factor-alpha (TNF-alpha) signal transduction through ceramide. Dissociation of growth inhibitory effects of TNF-alpha from activation of nuclear factor-kappa B. J Biol Chem 268:17762–17766

    CAS  PubMed  Google Scholar 

  117. Betts JC, Agranoff AB, Nabel GJ, Shayman JA (1994) Dissociation of endogenous cellular ceramide from NF-kappa B activation. J Biol Chem 269:8455–8458

    CAS  PubMed  Google Scholar 

  118. Colell A, García-Ruiz C, Roman J, Ballesta A, Fernández-Checa JC (2001) Ganglioside GD3 enhances apoptosis by suppressing the nuclear factor-kB-dependent survival pathway. FASEB J 15:1068–1070

    CAS  PubMed  Google Scholar 

  119. Paris R, Morales A, Coll O, Sánchez-Reyes A, García-Ruiz C, Fernández-Checa JC (2002) Ganglioside GD3 sensitizes human hepatoma cells to cancer therapy. J Biol Chem 277:49870–49876

    CAS  PubMed  Google Scholar 

  120. Malisan F, Franchi L, Tomassini B, Ventura N, Condo I, Rippo MR, Rufini A, Liberati L, Nachtigall C, Kniep B, Testi R (2002) Acetylation suppresses the proapoptotic activity of GD3 ganglioside. J Exp Med 196:1535–1541

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Mukherjee K, Chava AK, Mandal C, Dey SN, Kniep B, Chandra S, Mandal C (2008) O-acetylation of GD3 prevents its apoptotic effect and promotes survival of lymphoblasts in childhood acute lymphoblastic leukaemia. J Cell Biochem 105:724–734

    CAS  PubMed  Google Scholar 

  122. Birks SM, Danquah JO, King L, Vlasak R, Gorecki DC, Pilkington GJ (2011) Targeting the GD3 acetylation pathway selectively induces apoptosis in glioblastoma. Neuro-Oncology 13:950–960

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Cazet A, Groux-Degroote S, Teylaert B, Kwon K-M, Lehoux S, Slomianny C, Kim C-H, Le Bourhis X, Delannoy P (2009) GD3 synthase overexpression enhances proliferation and migration of MDA-MB-231 breast cancer cells. Biol Chem 390:601–609

    CAS  PubMed  Google Scholar 

  124. Lluis JM, Llacuna L, Von MC, Barcena C, Enrich C, Morales A, Fernandez-Checa JC (2009) GD3 synthase overexpression sensitizes hepatocarcinoma cells to hypoxia and reduces tumor growth by suppressing the cSrc/NF-kappaB survival pathway. PLoS ONE 4:e8059

    PubMed Central  PubMed  Google Scholar 

  125. Chen HY, Challa AK, Varki A (2006) 9-O-Acetylation of exogenously added ganglioside GD3: the GD3 molecule induces its own O-acetylation machinery. J Biol Chem 281:7825–7833

    CAS  PubMed  Google Scholar 

  126. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714

    CAS  PubMed  Google Scholar 

  127. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325:332–336

    CAS  PubMed  Google Scholar 

  128. Platt FM (2014) Sphingolipids lysosomal storage disorders. Nature 510:68–75

    CAS  PubMed  Google Scholar 

  129. Vitner EB, Salomon R, Farfel-Becker T, Meshcheriakova A, Ali M, Klein AD, Platt FM, Cox TM, Futerman AH (2014) RIPK3 as a potential therapeutic target for Gaucher’s disease. Nat Med 20:204–208

    CAS  PubMed  Google Scholar 

  130. Ryland LK, Fox TE, Liu X, Loughran TP, Kester M (2011) Dysregulation of sphingolipid metabolism in cancer. Cancer Biol Ther 11:138–149

    CAS  PubMed  Google Scholar 

  131. Tagaram HRS, Divittore NA, Barth BM, Kaiser JM, Avella D, Kimchi ET, Jiang Y, Isom HC, Kester M, Staveley-O’carroll KF (2011) Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut 60:695–701

    CAS  PubMed  Google Scholar 

  132. Garcia-Ruiz C, Mato JM, Vance D, Kaplowitz N, Fernández-Checa JC (2014) Acid sphingomyelinase-ceramide system in steatohepatitis: a novel target regulating multiple pathways. J Hepatol 62:219–233

    PubMed  Google Scholar 

  133. Grimm MO, Zimmwe VC, Lehmann J, Grimm H, Hartmann T (2013) The impact of cholesterol, DHA, and sphingolipids on Alzheimer’s disease. Biomed Res Int 2013:814390

    PubMed Central  PubMed  Google Scholar 

  134. Lee JK, Jin HK, Park MH, Kim BR, Lee PH, Nakauchi H, Carter JE, He X, Schuchman EH, Bae JS (2014) Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer’s disease. J Exp Med 211:1551–1570

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The work was supported by Grants SAF-2011-23031, SAF-2012-34831 from Plan Nacional de I+D, Spain, the center Grant P50-AA-11999 Research Center for Liver and Pancretic Diseases funded by NIAAA/NIH, a Grant from Fundació Marató de TV3, La Mutua Madrileña, PI11/0325 (META) Grant from the Instituto Salud Carlos III, and by the support of CIBEREHD.

Author information

Authors and Affiliations

  1. Department of Cell Death and Proliferation, Instituto Investigaciones Biomedicas de Barcelona, CSIC, Barcelona, Spain

    Carmen Garcia-Ruiz, Albert Morales & José C. Fernández-Checa

  2. Liver Unit-Hospital Clinic-IDIBAPS and Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain

    Carmen Garcia-Ruiz, Albert Morales & José C. Fernández-Checa

  3. University of Southern California Research Center for Liver Diseases, Keck School of Medicine, USC, Los Angeles, CA, USA

    Carmen Garcia-Ruiz & José C. Fernández-Checa

Authors
  1. Carmen Garcia-Ruiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Albert Morales
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. José C. Fernández-Checa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José C. Fernández-Checa.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garcia-Ruiz, C., Morales, A. & Fernández-Checa, J.C. Glycosphingolipids and cell death: one aim, many ways. Apoptosis 20, 607–620 (2015). https://doi.org/10.1007/s10495-015-1092-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-015-1092-6

Keywords

Search

Navigation