Defect of synthesis of very long-chain fatty acids confers resistance to growth inhibition by inositol phosphorylceramide synthase repression in yeast Saccharomyces cerevisiae.
Aureobasidin A (AbA) inhibits Aur1p, an enzyme catalysing the formation of inositol phosphorylceramide in the yeast Saccharomyces cerevisiae. AbA treatment results not only in reductions in complex sphingolipid levels but also in accumulation of ceramides, both of which are believed to lead to the growth defect caused by this inhibitor. We screened for mutants showing resistance to this drug, and found that a lack of ELO3, the gene involved in synthesis of very long-chain fatty acids, confers resistance to the inhibitor. The resistance as to growth inhibition by reduction in Aur1p activity was also confirmed by repression of AUR1 expression under the control of a tetracycline-regulatable promoter. Under the AUR1-repressive conditions, the ELO3 mutant showed reduction in the complex sphingolipid levels and the accumulation of ceramide, like wild-type cells. However, with repression of LCB1 encoding serine palmitoyltransferase or LIP1 encoding the ceramide synthase subunit, the ELO3 mutation did not confer resistance to growth inhibition induced by the impaired sphingolipid biosynthesis. Therefore, it is suggested that the ELO3 mutant shows resistance as to accumulation of ceramides, implying that the chain lengths of fatty acids in ceramide are a critical factor for the ceramide-induced growth defect under AUR1-repressive conditions.
Tani
Motohiro
M
Department of Chemistry, Faculty of Sciences; Institute for Advanced Study, Kyushu University, 6-10-1, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan. tani@chem.kyushu-univ.jp
Kuge
Osamu
O
D000123:Acetyltransferases; D003066:Coenzyme A Ligases / Q000235:genetics*; D047630:Depsipeptides / Q000494:pharmacology*; D025141:Drug Resistance, Fungal; D004794:Enzyme Repression; D006602:Hexosyltransferases / Q000037:antagonists & inhibitors*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D013107:Sphingolipids / Q000096:biosynthesis; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D047630:Depsipeptides; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids; C071398:aureobasidin A; D000123:Acetyltransferases; C107119:SUR4 protein, S cerevisiae; D006602:Hexosyltransferases; C088714:phosphatidylinositol-ceramide phosphoinositol transferase; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase