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Metabolism and Roles of Sphingolipids in Yeast Saccharomyces cerevisiae

  • Jihui Ren
  • Yusuf A. HannunEmail author
Reference work entry
Part of the Handbook of Hydrocarbon and Lipid Microbiology book series (HHLM)

Abstract

Sphingolipids are major membrane components of all eukaryotic cells. They are also important bioactive molecules involved in a plethora of essential cellular processes that are implicated in various human diseases. Most bioactive sphingolipids also serve as intermediate products of the sphingolipid metabolic network. It is thus critical to understand sphingolipid metabolic pathways in order to dissect sphingolipid function at single-species level. Here, we review in detail the biosynthetic and degradation pathways of sphingolipids in the yeast Saccharomyces cerevisiae, a model organism whose sphingolipid composition is rather simple but with conserved metabolic pathways and regulation mechanisms as higher eukaryotes. The functions of yeast sphingoid bases, ceramides, and complex sphingolipids are also discussed. Together, this knowledge provides a foundation to understand sphingolipid metabolism, their physiological roles, their potential as therapeutic targets for human diseases, and the major challenges the field is facing.

Notes

Acknowledgments

The authors would like to acknowledge Drs. Cungui Mao, Christopher Clarke, and Cosima Rhein for their critical discussions and valuable comments. Work related to this review in Dr. Hannun’s laboratory was supported by grant R35 GM118128.

References

  1. Almeida T, Marques M, Mojzita D, Amorim MA, Silva RD, Almeida B, Rodrigues P, Ludovico P, Hohmann S, Moradas-Ferreira P et al (2008) Isc1p plays a key role in hydrogen peroxide resistance and chronological lifespan through modulation of iron levels and apoptosis. Mol Biol Cell 19:865–876PubMedPubMedCentralCrossRefGoogle Scholar
  2. Barbosa AD, Pereira C, Osorio H, Moradas-Ferreira P, Costa V (2016) The ceramide-activated protein phosphatase Sit4p controls lifespan, mitochondrial function and cell cycle progression by regulating hexokinase 2 phosphorylation. Cell Cycle 15:1620–1630PubMedPubMedCentralCrossRefGoogle Scholar
  3. Beeler T, Bacikova D, Gable K, Hopkins L, Johnson C, Slife H, Dunn T (1998) The Saccharomyces cerevisiae TSC10/YBR265w gene encoding 3-ketosphinganine reductase is identified in a screen for temperature-sensitive suppressors of the Ca2+-sensitive csg2Delta mutant. J Biol Chem 273:30688–30694PubMedCrossRefGoogle Scholar
  4. Beeler TJ, Fu D, Rivera J, Monaghan E, Gable K, Dunn TM (1997) SUR1 (CSG1/BCL21), a gene necessary for growth of Saccharomyces cerevisiae in the presence of high Ca2+ concentrations at 37 degrees C, is required for mannosylation of inositolphosphorylceramide. Mol Gen Genet MGG 255:570–579PubMedCrossRefGoogle Scholar
  5. Beeler T, Gable K, Zhao C, Dunn T (1994) A novel protein, CSG2p, is required for Ca2+ regulation in Saccharomyces cerevisiae. J Biol Chem 269:7279–7284PubMedGoogle Scholar
  6. Bejaoui K, Uchida Y, Yasuda S, Ho M, Nishijima M, Brown RH Jr, Holleran WM, Hanada K (2002) Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis. J Clin Invest 110:1301–1308PubMedPubMedCentralCrossRefGoogle Scholar
  7. 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 14:542–547PubMedCrossRefGoogle Scholar
  8. Bosson R, Guillas I, Vionnet C, Roubaty C, Conzelmann A (2009) Incorporation of ceramides into Saccharomyces cerevisiae glycosylphosphatidylinositol-anchored proteins can be monitored in vitro. Eukaryot Cell 8:306–314PubMedCrossRefGoogle Scholar
  9. Breslow DK, Collins SR, Bodenmiller B, Aebersold R, Simons K, Shevchenko A, Ejsing CS, Weissman JS (2010) Orm family proteins mediate sphingolipid homeostasis. Nature 463:1048–1053PubMedPubMedCentralCrossRefGoogle Scholar
  10. Carter HE, Haines WJ et al (1947) Biochemistry of the sphingolipides; preparation of sphingolipides from beef brain and spinal cord. J Biol Chem 169:77–82PubMedGoogle Scholar
  11. Chatterjee S (1999) Neutral sphingomyelinase: past, present and future. Chem Phys Lipids 102:79–96PubMedCrossRefGoogle Scholar
  12. Chauhan N, Visram M, Cristobal-Sarramian A, Sarkleti F, Kohlwein SD (2015) Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression. Proc Natl Acad Sci U S A 112:E1077–E1085PubMedPubMedCentralCrossRefGoogle Scholar
  13. Chung N, Jenkins G, Hannun YA, Heitman J, Obeid LM (2000) Sphingolipids signal heat stress-induced ubiquitin-dependent proteolysis. J Biol Chem 275:17229–17232PubMedCrossRefGoogle Scholar
  14. Chung N, Mao C, Heitman J, Hannun YA, Obeid LM (2001) Phytosphingosine as a specific inhibitor of growth and nutrient import in Saccharomyces cerevisiae. J Biol Chem 276:35614–35621PubMedCrossRefGoogle Scholar
  15. Cowart LA, Gandy JL, Tholanikunnel B, Hannun YA (2010) Sphingolipids mediate formation of mRNA processing bodies during the heat-stress response of Saccharomyces cerevisiae. Biochem J 431:31–38PubMedPubMedCentralCrossRefGoogle Scholar
  16. Cowart LA, Okamoto Y, Pinto FR, Gandy JL, Almeida JS, Hannun YA (2003) Roles for sphingolipid biosynthesis in mediation of specific programs of the heat stress response determined through gene expression profiling. J Biol Chem 278:30328–30338PubMedCrossRefGoogle Scholar
  17. Cowart LA, Shotwell M, Worley ML, Richards AJ, Montefusco DJ, Hannun YA, Lu X (2010) Revealing a signaling role of phytosphingosine-1-phosphate in yeast. Mol Syst Biol 6:349PubMedPubMedCentralCrossRefGoogle Scholar
  18. D’Mello NP, Childress AM, Franklin DS, Kale SP, Pinswasdi C, Jazwinski SM (1994) Cloning and characterization of LAG1, a longevity-assurance gene in yeast. J Biol Chem 269:15451–15459PubMedGoogle Scholar
  19. deHart AK, Schnell JD, Allen DA, Hicke L (2002) The conserved Pkh-Ypk kinase cascade is required for endocytosis in yeast. J Cell Biol 156:241–248PubMedPubMedCentralCrossRefGoogle Scholar
  20. Denic V, Weissman JS (2007) A molecular caliper mechanism for determining very long-chain fatty acid length. Cell 130:663–677PubMedCrossRefGoogle Scholar
  21. Dickson RC (2008) Thematic review series: sphingolipids. New insights into sphingolipid metabolism and function in budding yeast. J Lipid Res 49:909–921PubMedPubMedCentralCrossRefGoogle Scholar
  22. Dickson RC, Lester RL (1999) Yeast sphingolipids. Biochim Biophys Acta 1426:347–357PubMedCrossRefGoogle Scholar
  23. Dickson RC, Nagiec EE, Skrzypek M, Tillman P, Wells GB, Lester RL (1997) Sphingolipids are potential heat stress signals in Saccharomyces. J Biol Chem 272:30196–30200PubMedCrossRefGoogle Scholar
  24. Dickson RC, Nagiec EE, Wells GB, Nagiec MM, Lester RL (1997) Synthesis of mannose-(inositol-P)2-ceramide, the major sphingolipid in Saccharomyces cerevisiae, requires the IPT1 (YDR072c) gene. J Biol Chem 272:29620–29625PubMedCrossRefGoogle Scholar
  25. Dobrowsky RT, Hannun YA (1993) Ceramide-activated protein phosphatase: partial purification and relationship to protein phosphatase 2A. Adv Lipid Res 25:91–104PubMedGoogle Scholar
  26. Dressler KA, Mathias S, Kolesnick RN (1992) Tumor necrosis factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system. Science 255:1715–1718PubMedCrossRefGoogle Scholar
  27. Edvardson S, Yi JK, Jalas C, Xu R, Webb BD, Snider J, Fedick A, Kleinman E, Treff NR, Mao C et al (2016) Deficiency of the alkaline ceramidase ACER3 manifests in early childhood by progressive leukodystrophy. J Med Genet 53:389–396PubMedPubMedCentralCrossRefGoogle Scholar
  28. Epstein S, Castillon G. A, Qin Y, Riezman H (2012) An essential function of sphingolipids in yeast cell division. Mol Microbiol 84:1018–32PubMedCrossRefGoogle Scholar
  29. Fishbein JD, Dobrowsky RT, Bielawska A, Garrett S, Hannun YA (1993) Ceramide-mediated growth inhibition and CAPP are conserved in Saccharomyces cerevisiae. J Biol Chem 268:9255–9261PubMedGoogle Scholar
  30. Friant S, Lombardi R, Schmelzle T, Hall MN, Riezman H (2001) Sphingoid base signaling via Pkh kinases is required for endocytosis in yeast. EMBO J 20:6783–6792PubMedPubMedCentralCrossRefGoogle Scholar
  31. Friant S, Zanolari B, Riezman H (2000) Increased protein kinase or decreased PP2A activity bypasses sphingoid base requirement in endocytosis. EMBO J 19:2834–2844PubMedPubMedCentralCrossRefGoogle Scholar
  32. Funato K, Riezman H (2001) Vesicular and nonvesicular transport of ceramide from ER to the Golgi apparatus in yeast. J Cell Biol 155:949–959PubMedPubMedCentralCrossRefGoogle Scholar
  33. Fyrst H, Saba JD (2008) Sphingosine-1-phosphate lyase in development and disease: sphingolipid metabolism takes flight. Biochim Biophys Acta 1781:448–458PubMedPubMedCentralCrossRefGoogle Scholar
  34. Gable K, Gupta SD, Han G, Niranjanakumari S, Harmon JM, Dunn TM (2010) A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity. J Biol Chem 285:22846–22852PubMedPubMedCentralCrossRefGoogle Scholar
  35. Gable K, Slife H, Bacikova D, Monaghan E, Dunn TM (2000) Tsc3p is an 80-amino acid protein associated with serine palmitoyltransferase and required for optimal enzyme activity. J Biol Chem 275:7597–7603PubMedCrossRefGoogle Scholar
  36. Gasch AP, Spellman PT, Kao CM, Carmel-Harel O, Eisen MB, Storz G, Botstein D, Brown PO (2000) Genomic expression programs in the response of yeast cells to environmental changes. Mol Biol Cell 11:4241–4257PubMedPubMedCentralCrossRefGoogle Scholar
  37. Grilley MM, Stock SD, Dickson RC, Lester RL, Takemoto JY (1998) Syringomycin action gene SYR2 is essential for sphingolipid 4-hydroxylation in Saccharomyces cerevisiae. J Biol Chem 273:11062–11068PubMedCrossRefGoogle Scholar
  38. Guillas I, Kirchman PA, Chuard R, Pfefferli M, Jiang JC, Jazwinski SM, Conzelmann A (2001) C26-CoA-dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p. EMBO J 20:2655–2665PubMedPubMedCentralCrossRefGoogle Scholar
  39. Haak D, Gable K, Beeler T, Dunn T (1997) Hydroxylation of Saccharomyces cerevisiae ceramides requires Sur2p and Scs7p. J Biol Chem 272:29704–29710PubMedCrossRefGoogle Scholar
  40. Hama H (2010) Fatty acid 2-Hydroxylation in mammalian sphingolipid biology. Biochim Biophys Acta 1801:405–414PubMedCrossRefGoogle Scholar
  41. Han G, Gable K, Kohlwein SD, Beaudoin F, Napier JA, Dunn TM (2002) The Saccharomyces cerevisiae YBR159w gene encodes the 3-ketoreductase of the microsomal fatty acid elongase. J Biol Chem 277:35440–35449PubMedCrossRefGoogle Scholar
  42. Han G, Gupta SD, Gable K, Niranjanakumari S, Moitra P, Eichler F, Brown RH Jr, Harmon JM, Dunn TM (2009) Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci U S A 106:8186–8191PubMedPubMedCentralCrossRefGoogle Scholar
  43. Han S, Lone MA, Schneiter R, Chang A (2010) Orm1 and Orm2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control. Proc Natl Acad Sci U S A 107:5851–5856PubMedPubMedCentralCrossRefGoogle Scholar
  44. Hanada K, Hara T, Nishijima M, Kuge O, Dickson RC, Nagiec MM (1997) A mammalian homolog of the yeast LCB1 encodes a component of serine palmitoyltransferase, the enzyme catalyzing the first step in sphingolipid synthesis. J Biol Chem 272:32108–32114PubMedCrossRefGoogle Scholar
  45. Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M, Nishijima M (2003) Molecular machinery for non-vesicular trafficking of ceramide. Nature 426:803–809PubMedCrossRefGoogle Scholar
  46. Hannun YA (1994) The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem 269:3125–3128PubMedGoogle Scholar
  47. Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139–150PubMedCrossRefGoogle Scholar
  48. Hannun YA, Loomis CR, Merrill AH Jr, Bell RM (1986) Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J Biol Chem 261:12604–12609PubMedGoogle Scholar
  49. Hannun YA, Obeid LM, Wolff RA (1993) The novel second messenger ceramide: identification, mechanism of action, and cellular activity. Adv Lipid Res 25:43–64PubMedGoogle Scholar
  50. Hla T, Lee MJ, Ancellin N, Paik JH, Kluk MJ (2001) Lysophospholipids – receptor revelations. Science 294:1875–1878PubMedCrossRefGoogle Scholar
  51. Huwiler A, Brunner J, Hummel R, Vervoordeldonk M, Stabel S, van den Bosch H, Pfeilschifter J (1996) Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase. Proc Natl Acad Sci U S A 93:6959–6963PubMedPubMedCentralCrossRefGoogle Scholar
  52. Hwang SY, Kim TH, Lee HH (2015) Neutral sphingomyelinase and breast cancer research. J Menopausal Med 21:24–27PubMedPubMedCentralCrossRefGoogle Scholar
  53. Ikeda M, Kihara A, Igarashi Y (2004) Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5′-phosphate binding domain exposed to the cytosol. Biochem Biophys Res Commun 325:338–343PubMedCrossRefGoogle Scholar
  54. Jenkins GM, Hannun YA (2001) Role for de novo sphingoid base biosynthesis in the heat-induced transient cell cycle arrest of Saccharomyces cerevisiae. J Biol Chem 276:8574–8581PubMedCrossRefGoogle Scholar
  55. Jenkins GM, Richards A, Wahl T, Mao C, Obeid L, Hannun Y (1997) Involvement of yeast sphingolipids in the heat stress response of Saccharomyces cerevisiae. J Biol Chem 272:32566–32572PubMedCrossRefGoogle Scholar
  56. Kanfer JN, Hakomori S-i (1983) Sphingolipid biochemistry. Plenum Press, New YorkCrossRefGoogle Scholar
  57. Kihara A (2012) Very long-chain fatty acids: elongation, physiology and related disorders. J Biochem 152:387–395PubMedCrossRefGoogle Scholar
  58. Kihara A, Igarashi Y (2004) FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site that faces the cytosolic side of the endoplasmic reticulum membrane. J Biol Chem 279:49243–49250PubMedCrossRefGoogle Scholar
  59. Kim MY, Linardic C, Obeid L, Hannun Y (1991) Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor alpha and gamma-interferon. Specific role in cell differentiation. J Biol Chem 266:484–489PubMedGoogle Scholar
  60. Kitagaki H, Cowart LA, Matmati N, Montefusco D, Gandy J, de Avalos SV, Novgorodov SA, Zheng J, Obeid LM, Hannun YA (2009) ISC1-dependent metabolic adaptation reveals an indispensable role for mitochondria in induction of nuclear genes during the diauxic shift in Saccharomyces cerevisiae. J Biol Chem 284:10818–10830PubMedPubMedCentralCrossRefGoogle Scholar
  61. Kitagaki H, Cowart LA, Matmati N, Vaena de Avalos S, Novgorodov SA, Zeidan YH, Bielawski J, Obeid LM, Hannun YA (2007) Isc1 regulates sphingolipid metabolism in yeast mitochondria. Biochim Biophys Acta 1768:2849–2861PubMedPubMedCentralCrossRefGoogle Scholar
  62. Kohlwein SD, Eder S, Oh CS, Martin CE, Gable K, Bacikova D, Dunn T (2001) Tsc13p is required for fatty acid elongation and localizes to a novel structure at the nuclear-vacuolar interface in Saccharomyces cerevisiae. Mol Cell Biol 21:109–125PubMedPubMedCentralCrossRefGoogle Scholar
  63. Kolesnick RN (1991) Sphingomyelin and derivatives as cellular signals. Prog Lipid Res 30:1–38PubMedCrossRefGoogle Scholar
  64. Kolesnick R, Golde DW (1994) The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell 77:325–328PubMedCrossRefGoogle Scholar
  65. Kolter T, Sandhoff K (2006) Sphingolipid metabolism diseases. Biochim Biophys Acta 1758:2057–2079PubMedCrossRefGoogle Scholar
  66. Krebs S, Medugorac I, Rother S, Strasser K, Forster M (2007) A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy. Proc Natl Acad Sci U S A 104:6746–6751PubMedPubMedCentralCrossRefGoogle Scholar
  67. Kumagai K, Yasuda S, Okemoto K, Nishijima M, Kobayashi S, Hanada K (2005) CERT mediates intermembrane transfer of various molecular species of ceramides. J Biol Chem 280:6488–6495PubMedCrossRefGoogle Scholar
  68. Levy M, Futerman AH (2010) Mammalian ceramide synthases. IUBMB Life 62:347–356PubMedPubMedCentralCrossRefGoogle Scholar
  69. Liao HC, Chen MY (2012) Target of rapamycin complex 2 signals to downstream effector yeast protein kinase 2 (Ypk2) through adheres-voraciously-to-target-of-rapamycin-2 protein 1 (Avo1) in Saccharomyces cerevisiae. J Biol Chem 287:6089–6099PubMedCrossRefGoogle Scholar
  70. Liu J, Mathias S, Yang Z, Kolesnick RN (1994) Renaturation and tumor necrosis factor-alpha stimulation of a 97-kDa ceramide-activated protein kinase. J Biol Chem 269:3047–3052PubMedGoogle Scholar
  71. Liu K, Zhang X, Lester RL, Dickson RC (2005) The sphingoid long chain base phytosphingosine activates AGC-type protein kinases in Saccharomyces cerevisiae including Ypk1, Ypk2, and Sch9. J Biol Chem 280:22679–22687PubMedCrossRefGoogle Scholar
  72. Mandala SM, Thornton R, Galve-Roperh I, Poulton S, Peterson C, Olivera A, Bergstrom J, Kurtz MB, Spiegel S (2000) Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine-1- phosphate and induces cell death. Proc Natl Acad Sci U S A 97:7859–7864PubMedPubMedCentralCrossRefGoogle Scholar
  73. Mao C, Xu R, Bielawska A, Obeid LM (2000) Cloning of an alkaline ceramidase from Saccharomyces cerevisiae. An enzyme with reverse (CoA-independent) ceramide synthase activity. J Biol Chem 275:6876–6884PubMedCrossRefGoogle Scholar
  74. Mao C, Xu R, Bielawska A, Szulc ZM, Obeid LM (2000) Cloning and characterization of a Saccharomyces cerevisiae alkaline ceramidase with specificity for dihydroceramide. J Biol Chem 275:31369–31378PubMedCrossRefGoogle Scholar
  75. Mao C, Wadleigh M, Jenkins GM, Hannun YA, Obeid LM (1997) Identification and characterization of Saccharomyces cerevisiae dihydrosphingosine-1-phosphate phosphatase. J Biol Chem 272:28690–28694PubMedCrossRefGoogle Scholar
  76. Mao C, Xu R, Szulc ZM, Bielawska A, Galadari SH, Obeid LM (2001) Cloning and characterization of a novel human alkaline ceramidase. A mammalian enzyme that hydrolyzes phytoceramide. J Biol Chem 276:26577–26588PubMedCrossRefGoogle Scholar
  77. Matmati N, Kitagaki H, Montefusco D, Mohanty BK, Hannun YA (2009) Hydroxyurea sensitivity reveals a role for ISC1 in the regulation of G2/M. J Biol Chem 284:8241–8246PubMedPubMedCentralCrossRefGoogle Scholar
  78. Matmati N, Metelli A, Tripathi K, Yan S, Mohanty BK, Hannun YA (2013) Identification of C18:1-phytoceramide as the candidate lipid mediator for hydroxyurea resistance in yeast. J Biol Chem 288:17272–17284PubMedPubMedCentralCrossRefGoogle Scholar
  79. Meier KD, Deloche O, Kajiwara K, Funato K, Riezman H (2006) Sphingoid base is required for translation initiation during heat stress in Saccharomyces cerevisiae. Mol Biol Cell 17:1164–1175PubMedPubMedCentralCrossRefGoogle Scholar
  80. Merrill AH Jr, Sereni AM, Stevens VL, Hannun YA, Bell RM, Kinkade JM Jr (1986) Inhibition of phorbol ester-dependent differentiation of human promyelocytic leukemic (HL-60) cells by sphinganine and other long-chain bases. J Biol Chem 261:12610–12615PubMedGoogle Scholar
  81. Montefusco DJ, Chen L, Matmati N, Lu S, Newcomb B, Cooper GF, Hannun YA, Lu X (2013) Distinct signaling roles of ceramide species in yeast revealed through systematic perturbation and systems biology analyses. Sci Signal 6:rs14PubMedPubMedCentralCrossRefGoogle Scholar
  82. Montefusco DJ, Newcomb B, Gandy JL, Brice SE, Matmati N, Cowart LA, Hannun YA (2012) Sphingoid bases and the serine catabolic enzyme CHA1 define a novel feedforward/feedback mechanism in the response to serine availability. J Biol Chem 287:9280–9289PubMedPubMedCentralCrossRefGoogle Scholar
  83. Muir A, Ramachandran S, Roelants FM, Timmons G, Thorner J (2014) TORC2-dependent protein kinase Ypk1 phosphorylates ceramide synthase to stimulate synthesis of complex sphingolipids. eLife 3:1–34Google Scholar
  84. Munn AL, Riezman H (1994) Endocytosis is required for the growth of vacuolar H(+)-ATPase-defective yeast: identification of six new END genes. J Cell Biol 127:373–386PubMedCrossRefGoogle Scholar
  85. Nagiec MM, Baltisberger JA, Wells GB, Lester RL, Dickson RC (1994) The LCB2 gene of Saccharomyces and the related LCB1 gene encode subunits of serine palmitoyltransferase, the initial enzyme in sphingolipid synthesis. Proc Natl Acad Sci U S A 91:7899–7902PubMedPubMedCentralCrossRefGoogle Scholar
  86. Nagiec MM, Nagiec EE, Baltisberger JA, Wells GB, Lester RL, Dickson RC (1997) Sphingolipid synthesis as a target for antifungal drugs. Complementation of the inositol phosphorylceramide synthase defect in a mutant strain of Saccharomyces cerevisiae by the AUR1 gene. J Biol Chem 272:9809–9817PubMedCrossRefGoogle Scholar
  87. Nagiec MM, Skrzypek M, Nagiec EE, Lester RL, Dickson RC (1998) The LCB4 (YOR171c) and LCB5 (YLR260w) genes of Saccharomyces encode sphingoid long chain base kinases. J Biol Chem 273:19437–19442PubMedCrossRefGoogle Scholar
  88. Nickels JT, Broach JR (1996) A ceramide-activated protein phosphatase mediates ceramide-induced G1 arrest of Saccharomyces cerevisiae. Genes Dev 10:382–394PubMedCrossRefGoogle Scholar
  89. Niles BJ, Powers T (2012) Plasma membrane proteins Slm1 and Slm2 mediate activation of the AGC kinase Ypk1 by TORC2 and sphingolipids in S. cerevisiae. Cell Cycle 11:3745–3749PubMedPubMedCentralCrossRefGoogle Scholar
  90. Niles BJ, Mogri H, Hill A, Vlahakis A, Powers T (2012) Plasma membrane recruitment and activation of the AGC kinase Ypk1 is mediated by target of rapamycin complex 2 (TORC2) and its effector proteins Slm1 and Slm2. Proc Natl Acad Sci U S A 109:1536–1541PubMedPubMedCentralCrossRefGoogle Scholar
  91. Obeid LM, Linardic CM, Karolak LA, Hannun YA (1993) Programmed cell death induced by ceramide. Science 259:1769–1771PubMedCrossRefGoogle Scholar
  92. Oh CS, Toke DA, Mandala S, Martin CE (1997) ELO2 and ELO3, homologues of the Saccharomyces cerevisiae ELO1 gene, function in fatty acid elongation and are required for sphingolipid formation. J Biol Chem 272:17376–17384PubMedCrossRefGoogle Scholar
  93. Olson DK, Frohlich F, Farese RV Jr, Walther TC (2016) Taming the sphinx: mechanisms of cellular sphingolipid homeostasis. Biochim Biophys Acta 1861:784–792PubMedCrossRefGoogle Scholar
  94. Park JH, Schuchman EH (2006) Acid ceramidase and human disease. Biochim Biophys Acta 1758:2133–2138PubMedCrossRefGoogle Scholar
  95. Patton JL, Lester RL (1991) The phosphoinositol sphingolipids of Saccharomyces cerevisiae are highly localized in the plasma membrane. J Bacteriol 173:3101–3108PubMedPubMedCentralCrossRefGoogle Scholar
  96. Penno A, Reilly MM, Houlden H, Laura M, Rentsch K, Niederkofler V, Stoeckli ET, Nicholson G, Eichler F, Brown RH Jr et al (2010) Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem 285:11178–11187PubMedPubMedCentralCrossRefGoogle Scholar
  97. Percy AK, Carson MA, Moore JF, Waechter CJ (1984) Control of phosphatidylethanolamine metabolism in yeast: diacylglycerol ethanolaminephosphotransferase and diacylglycerol cholinephosphotransferase are separate enzymes. Arch Biochem Biophys 230:69–81PubMedCrossRefGoogle Scholar
  98. Pralhada Rao R, Vaidyanathan N, Rengasamy M, Mammen Oommen A, Somaiya N, Jagannath MR (2013) Sphingolipid metabolic pathway: an overview of major roles played in human diseases. J Lipids 2013:178910PubMedPubMedCentralCrossRefGoogle Scholar
  99. Qie L, Nagiec MM, Baltisberger JA, Lester RL, Dickson RC (1997) Identification of a Saccharomyces gene, LCB3, necessary for incorporation of exogenous long chain bases into sphingolipids. J Biol Chem 272:16110–16117PubMedCrossRefGoogle Scholar
  100. 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 U S A 108:19222–19227PubMedPubMedCentralCrossRefGoogle Scholar
  101. Saba JD, Nara F, Bielawska A, Garrett S, Hannun YA (1997) The BST1 gene of Saccharomyces cerevisiae is the sphingosine-1-phosphate lyase. J Biol Chem 272:26087–26090PubMedCrossRefGoogle Scholar
  102. Sawai H, Okamoto Y, Luberto C, Mao C, Bielawska A, Domae N, Hannun YA (2000) Identification of ISC1 (YER019w) as inositol phosphosphingolipid phospholipase C in Saccharomyces cerevisiae. J Biol Chem 275:39793–39798PubMedCrossRefGoogle Scholar
  103. Schneiter R (1999) Brave little yeast, please guide us to thebes: sphingolipid function in S. cerevisiae. BioEssays: News Rev Mol, Cell Dev Biol 21:1004–1010CrossRefGoogle Scholar
  104. Schorling S, Vallee B, Barz WP, Riezman H, Oesterhelt D (2001) Lag1p and Lac1p are essential for the Acyl-CoA-dependent ceramide synthase reaction in Saccharomyces cerevisae. Mol Biol Cell 12:3417–3427PubMedPubMedCentralCrossRefGoogle Scholar
  105. Schuchman EH (2010) Acid sphingomyelinase, cell membranes and human disease: lessons from Niemann-Pick disease. FEBS Lett 584:1895–1900PubMedCrossRefGoogle Scholar
  106. Schuldiner M, Collins SR, Thompson NJ, Denic V, Bhamidipati A, Punna T, Ihmels J, Andrews B, Boone C, Greenblatt JF et al (2005) Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile. Cell 123:507–519PubMedCrossRefGoogle Scholar
  107. Shimobayashi M, Oppliger W, Moes S, Jeno P, Hall MN (2013) TORC1-regulated protein kinase Npr1 phosphorylates Orm to stimulate complex sphingolipid synthesis. Mol Biol Cell 24:870–881PubMedPubMedCentralCrossRefGoogle Scholar
  108. Skrzypek MS, Nagiec MM, Lester RL, Dickson RC (1998) Inhibition of amino acid transport by sphingoid long chain bases in Saccharomyces cerevisiae. J Biol Chem 273:2829–2834PubMedCrossRefGoogle Scholar
  109. Strub GM, Maceyka M, Hait NC, Milstien S, Spiegel S (2010) Extracellular and intracellular actions of sphingosine-1-phosphate. Adv Exp Med Biol 688:141–155PubMedPubMedCentralCrossRefGoogle Scholar
  110. Sun Y, Miao Y, Yamane Y, Zhang C, Shokat KM, Takematsu H, Kozutsumi Y, Drubin DG (2012) Orm protein phosphoregulation mediates transient sphingolipid biosynthesis response to heat stress via the Pkh-Ypk and Cdc55-PP2A pathways. Mol Biol Cell 23:2388–2398PubMedPubMedCentralCrossRefGoogle Scholar
  111. Sun Y, Taniguchi R, Tanoue D, Yamaji T, Takematsu H, Mori K, Fujita T, Kawasaki T, Kozutsumi Y (2000) Sli2 (Ypk1), a homologue of mammalian protein kinase SGK, is a downstream kinase in the sphingolipid-mediated signaling pathway of yeast. Mol Cell Biol 20:4411–4419PubMedPubMedCentralCrossRefGoogle Scholar
  112. Tabuchi M, Audhya A, Parsons AB, Boone C, Emr SD (2006) The phosphatidylinositol 4,5-biphosphate and TORC2 binding proteins Slm1 and Slm2 function in sphingolipid regulation. Mol Cell Biol 26:5861–5875PubMedPubMedCentralCrossRefGoogle Scholar
  113. Teixeira V, Medeiros TC, Vilaca R, Pereira AT, Chaves SR, Corte-Real M, Moradas-Ferreira P, Costa V (2015) Ceramide signalling impinges on Sit4p and Hog1p to promote mitochondrial fission and mitophagy in Isc1p-deficient cells. Cell Signal 27:1840–1849PubMedCrossRefGoogle Scholar
  114. Vaena de Avalos S, Okamoto Y, Hannun YA (2004) Activation and localization of inositol phosphosphingolipid phospholipase C, Isc1p, to the mitochondria during growth of Saccharomyces cerevisiae. J Biol Chem 279:11537–11545PubMedCrossRefGoogle Scholar
  115. Vallee B, Riezman H (2005) Lip1p: a novel subunit of acyl-CoA ceramide synthase. EMBO J 24:730–741PubMedPubMedCentralCrossRefGoogle Scholar
  116. Villasmil ML, Francisco J, Gallo-Ebert C, Donigan M, Liu HY, Brower M, Nickels JT Jr (2016) Ceramide signals for initiation of yeast mating-specific cell cycle arrest. Cell Cycle 15:441–454PubMedPubMedCentralCrossRefGoogle Scholar
  117. Watanabe R, Funato K, Venkataraman K, Futerman AH, Riezman H (2002) Sphingolipids are required for the stable membrane association of glycosylphosphatidylinositol-anchored proteins in yeast. J Biol Chem 277:49538–49544PubMedCrossRefGoogle Scholar
  118. Wilson E, Olcott MC, Bell RM, Merrill AH Jr, Lambeth JD (1986) Inhibition of the oxidative burst in human neutrophils by sphingoid long-chain bases. Role of protein kinase C in activation of the burst. J Biol Chem 261:12616–12623PubMedGoogle Scholar
  119. Yi JK, Xu R, Jeong E, Mileva I, Truman JP, Lin CL, Wang K, Snider J, Wen S, Obeid LM et al (2016) Aging-related elevation of sphingoid bases shortens yeast chronological life span by compromising mitochondrial function. Oncotarget 7:21124–21144PubMedPubMedCentralGoogle Scholar
  120. Zanolari B, Friant S, Funato K, Sutterlin C, Stevenson BJ, Riezman H (2000) Sphingoid base synthesis requirement for endocytosis in Saccharomyces cerevisiae. EMBO J 19:2824–2833PubMedPubMedCentralCrossRefGoogle Scholar
  121. Zhao C, Beeler T, Dunn T (1994) Suppressors of the Ca(2+)-sensitive yeast mutant (csg2) identify genes involved in sphingolipid biosynthesis. Cloning and characterization of SCS1, a gene required for serine palmitoyltransferase activity. J Biol Chem 269:21480–21488PubMedGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Stony Brook Cancer CenterStony Brook University, Health Science CenterStony BrookUSA

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