Aureobasidin A arrests growth of yeast cells through both ceramide intoxication and deprivation of essential inositolphosphorylceramides
Aureobasidin A arrests growth of yeast cells through both ceramide intoxication and deprivation of essential inositolphosphorylceramides
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DOI：
10.1111/j.1365-2958.2009.06628.x
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发表时间：
2009-03-01
影响因子：
3.6
通讯作者：
Conzelmann, Andreas
中科院分区：
文献类型：
--
作者：
Cerantola, Vanessa;Guillas, Isabelle;Conzelmann, Andreas
所有成熟的酿酒酵母鞘脂都含有含有C26:0或C24:0脂肪酸和植鞘苷或二氢鞘苷的肌醇磷酸化神经酰胺。在这里，我们分析了缺乏酰基辅酶a依赖性神经酰胺合成的lag1 δ lac1 δ突变体的脂质谱，这种突变体需要过度表达的Ydc1p的反神经酰胺酶活性来进行鞘脂的生物合成和生存。这些细胞被称为2 δ。YDC1产生的鞘脂只含有二氢鞘脂和一种异常宽的含有18到26个碳原子的脂肪酸。和野生型细胞一样，2 δ。YDC1细胞暴露于Aureobasidin A（一种肌醇磷酸化神经酰胺合成酶AUR1的抑制剂）时停止生长，但它们的神经酰胺水平仍然很低。这一发现反驳了目前的假设，即酵母细胞不需要肌醇磷酸化神经酰胺，在AbA存在下死亡只是因为神经酰胺积累到有毒浓度。此外，据报道具有AbA抗性的W303lag1 Delta lac1 Delta ypc1 Delta ydc1 Delta细胞在一定数量的细胞分裂后停止在AbA上生长，这很可能是因为AbA阻断了异常肌醇磷酸化鞘苷的生物合成。因此，数据表明酵母的肌醇磷酸化神经酰胺，相当于哺乳动物的鞘磷脂，对生长至关重要。数据还清楚地证实，野生型菌株在暴露于AbA时，由于神经酰胺中毒而立即停止生长，而早在肌醇磷酸化神经酰胺水平达到亚临界水平之前。
All mature Saccharomyces cerevisiae sphingolipids comprise inositolphosphorylceramides containing C26:0 or C24:0 fatty acids and either phytosphingosine or dihydrosphingosine. Here we analysed the lipid profile of lag1 Delta lac1 Delta mutants lacking acyl-CoA-dependent ceramide synthesis, which require the reverse ceramidase activity of overexpressed Ydc1p for sphingolipid biosynthesis and viability. These cells, termed 2 Delta. YDC1, make sphingolipids containing exclusively dihydrosphingosine and an abnormally wide spectrum of fatty acids with between 18 and 26 carbon atoms. Like wild-type cells, 2 Delta. YDC1 cells stop growing when exposed to Aureobasidin A (AbA), an inhibitor of the inositolphosphorylceramide synthase AUR1, yet their ceramide levels remain very low. This finding argues against a current hypothesis saying that yeast cells do not require inositolphosphorylceramides and die in the presence of AbA only because ceramides build up to toxic concentrations. Moreover, W303lag1 Delta lac1 Delta ypc1 Delta ydc1 Delta cells, reported to be AbA resistant, stop growing on AbA after a certain number of cell divisions, most likely because AbA blocks the biosynthesis of anomalous inositolphosphorylsphingosides. Thus, data argue that inositolphosphorylceramides of yeast, the equivalent of mammalian sphingomyelins, are essential for growth. Data also clearly confirm that wild-type strains, when exposed to AbA, immediately stop growing because of ceramide intoxication, long before inositolphosphorylceramide levels become subcritical.