Current Genetics

, Volume 64, Issue 5, pp 1021–1028 | Cite as

Protection mechanisms against aberrant metabolism of sphingolipids in budding yeast

  • Motohiro TaniEmail author
  • Kouichi Funato


Life is dependent on the protection of cellular functions from various stresses. Sphingolipids are essential biomembrane components in eukaryotic organisms, which are exposed to risks that may disrupt sphingolipid metabolism, threatening their lives. Defects of the sphingolipid biosynthesis pathway cause profound defects of various cellular functions and ultimately cell death. Therefore, cells are equipped with defense response mechanisms against aberrant metabolism of sphingolipids, the most characterized one being the target of rapamycin complex 2-mediated regulation of sphingolipid biosynthesis in budding yeast Saccharomyces cerevisiae. On the other hand, very recently, we found that the high osmolarity glycerol pathway is involved in suppression of a growth defect caused by a reduction in complex sphingolipid levels in yeast. It is suggested that this signaling pathway is not involved in the repair of the impaired biosynthesis pathway for sphingolipids, but compensates for cellular dysfunctions caused by reduction in complex sphingolipid levels. This is a novel protection mechanism against aberrant metabolism of complex sphingolipids, and further investigation of the mechanism will provide new insights into the physiological significance of complex sphingolipids. Here, we summarize the response signaling against breakdown of sphingolipid biosynthesis in yeast, which includes the high osmolarity glycerol pathway.


Sphingolipids Complex sphingolipids Ceramides Saccharomyces cerevisiae HOG pathway 


  1. Annan RB, Wu C, Waller DD, Whiteway M, Thomas DY (2008) Rho5p is involved in mediating the osmotic stress response in Saccharomyces cerevisiae, and its activity is regulated via Msi1p and Npr1p by phosphorylation and ubiquitination. Eukaryot Cell 7:1441–1449. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bicknell AA, Tourtellotte J, Niwa M (2010) Late phase of the endoplasmic reticulum stress response pathway is regulated by Hog1 MAP kinase. J Biol Chem 285:17545–17555. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Brewster JL, Gustin MC (2014) Hog1: 20 years of discovery and impact. Sci Signal 7:re7. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Capaldi AP, Kaplan T, Liu Y, Habib N, Regev A, Friedman N, O’Shea EK (2008) Structure and function of a transcriptional network activated by the MAPK Hog1. Nat Genet 40:1300–1306. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chi Y, Huddleston MJ, Zhang X, Young RA, Annan RS, Carr SA, Deshaies RJ (2001) Negative regulation of Gcn4 and Msn2 transcription factors by Srb10 cyclin-dependent kinase. Genes Dev 15:1078–1092. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cowart LA, Hannun YA (2007) Selective substrate supply in the regulation of yeast de novo sphingolipid synthesis. J Biol Chem 282:12330–12340. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Dickson RC (2008) Thematic review series: sphingolipids. New insights into sphingolipid metabolism and function in budding yeast. J Lipid Res 49:909–921. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Dickson RC, Sumanasekera C, Lester RL (2006) Functions and metabolism of sphingolipids in Saccharomyces cerevisiae. Prog Lipid Res 45:447–465. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Frohlich F, Petit C, Kory N, Christiano R, Hannibal-Bach HK, Graham M, Liu XR, Ejsing CS, Farese RV, Walther TC (2015) The GARP complex is required for cellular sphingolipid homeostasis. Elife 4:e08712. CrossRefGoogle Scholar
  13. Funato K, Riezman H (2001) Vesicular and nonvesicular transport of ceramide from ER to the Golgi apparatus in yeast. J Cell Biol 155:949–959. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Gururaj C, Federman RS, Chang A (2013) Orm proteins integrate multiple signals to maintain sphingolipid homeostasis. J Biol Chem 288:20453–20463. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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 USA 107:5851–5856. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Hatakeyama R, Kono K, Yoshida S (2017) Ypk1 and Ypk2 kinases maintain Rho1 at the plasma membrane by flippase-dependent lipid remodeling after membrane stresses. J Cell Sci 130:1169–1178. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ito M, Okino N, Tani M (2014) New insight into the structure, reaction mechanism, and biological functions of neutral ceramidase. Biochim Biophys Acta 1841:682–691. CrossRefPubMedGoogle Scholar
  18. 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 272:32566–32572CrossRefPubMedCentralGoogle Scholar
  19. Kajiwara K, Muneoka T, Watanabe Y, Karashima T, Kitagaki H, Funato K (2012) Perturbation of sphingolipid metabolism induces endoplasmic reticulum stress-mediated mitochondrial apoptosis in budding yeast. Mol Microbiol 86:1246–1261. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Kajiwara K, Ikeda A, Aguilera-Romero A, Castillon GA, Kagiwada S, Hanada K, Riezman H, Muniz M, Funato K (2014) Osh proteins regulate COPII-mediated vesicular transport of ceramide from the endoplasmic reticulum in budding yeast. J Cell Sci 127:376–387. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Komori H, Ichikawa S, Hirabayashi Y, Ito M (1999) Regulation of intracellular ceramide content in B16 melanoma cells—biological implications of ceramide glycosylation. J Biol Chem 274:8981–8987. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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 280:22679–22687. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Liu LK, Choudhary V, Toulmay A, Prinz WA (2017) An inducible ER-Golgi tether facilitates ceramide transport to alleviate lipotoxicity. J Cell Biol 216:131–147. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Maeda T, Takekawa M, Saito H (1995) Activation of yeast PBS2 MAPKK by MAPKKKs or by binding of an SH3-containing osmosensor. Science 269:554–558CrossRefPubMedCentralGoogle Scholar
  25. Mandala SM, Thornton RA, Frommer BR, Curotto JE, Rozdilsky W, Kurtz MB, Giacobbe RA, Bills GF, Cabello MA, Martin I et al (1995) The discovery of australifungin, a novel inhibitor of sphinganine N-acyltransferase from Sporormiella australis. Producing organism, fermentation, isolation, and biological activity. J Antibiot (Tokyo) 48:349–356CrossRefGoogle Scholar
  26. Miyake Y, Kozutsumi Y, Nakamura S, Fujita T, Kawasaki T (1995) Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin. Biochem Biophys Res Commun 211:396–403. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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 287:9280–9289. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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:e03779. CrossRefGoogle Scholar
  29. 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 272:9809–9817CrossRefPubMedCentralGoogle Scholar
  30. Nakahara K, Ohkuni A, Kitamura T, Abe K, Naganuma T, Ohno Y, Zoeller RA, Kihara A (2012) The Sjogren–Larsson syndrome gene encodes a hexadecenal dehydrogenase of the sphingosine 1-phosphate degradation pathway. Mol Cell 46:461–471. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Pina F, Yagisawa F, Obara K, Gregerson JD, Kihara A, Niwa M (2018) Sphingolipids activate the endoplasmic reticulum stress surveillance pathway. J Cell Biol 217:495–505. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Pittet M, Uldry D, Aebi M, Conzelmann A (2006) The N-glycosylation defect of cwh8 Delta yeast cells causes a distinct defect in sphingolipid biosynthesis. Glycobiology 16:155–164. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Roelants FM, Baltz AG, Trott AE, Fereres S, Thorner J (2010) A protein kinase network regulates the function of aminophospholipid flippases. Proc Natl Acad Sci USA 107:34–39. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 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 USA 108:19222–19227. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Schmitz HP, Jendretzki A, Wittland J, Wiechert J, Heinisch JJ (2015) Identification of Dck1 and Lmo1 as upstream regulators of the small GTPase Rho5 in Saccharomyces cerevisiae. Mol Microbiol 96:306–324. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Schuchman EH, Simonaro CM (2013) The genetics of sphingolipid hydrolases and sphingolipid storage diseases. Handb Exp Pharmacol. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Senkal CE, Salama MF, Snider AJ, Allopenna JJ, Rana NA, Koller A, Hannun YA, Obeid LM (2017) Ceramide Is metabolized to acylceramide and stored in lipid droplets. Cell Metab 25:686–697. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Simons K, Sampaio JL (2011) Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol 3:a004697. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 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 23:2388–2398. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Swinnen E, Wilms T, Idkowiak-Baldys J, Smets B, De Snijder P, Accardo S, Ghillebert R, Thevissen K, Cammue B, De Vos D, Bielawski J, Hannun YA, Winderickx J (2014) The protein kinase Sch9 is a key regulator of sphingolipid metabolism in Saccharomyces cerevisiae. Mol Biol Cell 25:196–211. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Tani M, Kuge O (2010) Requirement of a specific group of sphingolipid-metabolizing enzyme for growth of yeast Saccharomyces cerevisiae under impaired metabolism of glycerophospholipids. Mol Microbiol 78:395–413. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Tani M, Kuge O (2012) Involvement of complex sphingolipids and phosphatidylserine in endosomal trafficking in yeast Saccharomyces cerevisiae. Mol Microbiol 86:1262–1280. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Tani M, Toume M (2015) Alteration of complex sphingolipid composition and its physiological significance in yeast Saccharomyces cerevisiae lacking vacuolar ATPase. Microbiology 161:2369–2383. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Tanigawa M, Kihara A, Terashima M, Takahara T, Maeda T (2012) Sphingolipids regulate the yeast high-osmolarity glycerol response pathway. Mol Cell Biol 32:2861–2870. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Vilaca R, Barros I, Matmati N, Silva E, Martins T, Teixeira V, Hannun YA, Costa V (2018) The ceramide activated protein phosphatase Sit4 impairs sphingolipid dynamics, mitochondrial function and lifespan in a yeast model of Niemann-Pick type C1. Biochim Biophys Acta 1864:79–88. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Voynova NS, Vionnet C, Ejsing CS, Conzelmann A (2012) A novel pathway of ceramide metabolism in Saccharomyces cerevisiae. Biochem J 447:103–114. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Voynova NS, Roubaty C, Vazquez HM, Mallela SK, Ejsing CS, Conzelmann A (2015) Saccharomyces cerevisiae is dependent on vesicular traffic between the golgi apparatus and the vacuole when inositolphosphorylceramide synthase Aur1 is inactivated. Eukaryot Cell 14:1203–1216. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Winkler A, Arkind C, Mattison CP, Burkholder A, Knoche K, Ota I (2002) Heat stress activates the yeast high-osmolarity glycerol mitogen-activated protein kinase pathway, and protein tyrosine phosphatases are essential under heat stress. Eukaryot Cell 1:163–173CrossRefPubMedCentralGoogle Scholar
  49. Yamaguchi Y, Katsuki Y, Tanaka S, Kawaguchi R, Denda H, Ikeda T, Funato K, Tani M (2018) Protective role of the HOG pathway against the growth defect caused by impaired biosynthesis of complex sphingolipids in yeast Saccharomyces cerevisiae. Mol Microbiol 107:363–386. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Biofunctional Science and Technology, Graduate School of Biosphere ScienceHiroshima UniversityHigashi-HiroshimaJapan

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