Functional Biology, KU Leuven, 3001 Heverlee, Belgium Centre for Surface Chemistry and Catalysis, KU Leuven, 3001 Heverlee, Belgium Centre of Microbial and Plant Genetics, KU Leuven, 3001 Heverlee, Belgium Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29403.
Mol Biol Cell. 2014 Jan;25(1):196-211. doi: 10.1091/mbc.E13-06-0340. Epub 2013 Nov 6.
The Saccharomyces cerevisiae protein kinase Sch9 is an in vitro and in vivo effector of sphingolipid signaling. This study examines the link between Sch9 and sphingolipid metabolism in S. cerevisiae in vivo based on the observation that the sch9Δ mutant displays altered sensitivity to different inhibitors of sphingolipid metabolism, namely myriocin and aureobasidin A. Sphingolipid profiling indicates that sch9Δ cells have increased levels of long-chain bases and long-chain base-1 phosphates, decreased levels of several species of (phyto)ceramides, and altered ratios of complex sphingolipids. We show that the target of rapamycin complex 1-Sch9 signaling pathway functions to repress the expression of the ceramidase genes YDC1 and YPC1, thereby revealing, for the first time in yeast, a nutrient-dependent transcriptional mechanism involved in the regulation of sphingolipid metabolism. In addition, we establish that Sch9 affects the activity of the inositol phosphosphingolipid phospholipase C, Isc1, which is required for ceramide production by hydrolysis of complex sphingolipids. Given that sphingolipid metabolites play a crucial role in the regulation of stress tolerance and longevity of yeast cells, our data provide a model in which Sch9 regulates the latter phenotypes by acting not only as an effector but also as a regulator of sphingolipid metabolism.
酿酒酵母蛋白激酶 Sch9 是鞘脂信号的体外和体内效应物。本研究基于以下观察结果，即在体内考察 Sch9 与酿酒酵母鞘脂代谢之间的联系：sch9Δ 突变体对不同鞘脂代谢抑制剂（即甘露庚酮糖和 aureobasidin A）的敏感性发生改变。鞘脂分析表明，sch9Δ 细胞中长链碱基和长链碱基-1 磷酸的水平升高，几种（植物）神经酰胺的水平降低，并且复杂鞘脂的比例发生改变。我们表明，雷帕霉素复合物 1-Sch9 信号通路的靶标作用是抑制神经酰胺酶基因 YDC1 和 YPC1 的表达，从而首次在酵母中揭示了参与调节鞘脂代谢的营养依赖性转录机制。此外，我们确定 Sch9 影响肌醇磷酸神经酰胺酶的活性，Isc1，它是通过水解复杂鞘脂产生神经酰胺所必需的。鉴于鞘脂代谢物在酵母细胞的应激耐受和寿命调节中起着至关重要的作用，我们的数据提供了一个模型，其中 Sch9 通过不仅作为效应物而且作为鞘脂代谢的调节剂来调节后一表型。
