Aronova Sofia, Wedaman Karen, Aronov Pavel A, Fontes Kristin, Ramos Karmela, Hammock Bruce D, Powers Ted
Section of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, CA 95616, USA.
Cell Metab. 2008 Feb;7(2):148-58. doi: 10.1016/j.cmet.2007.11.015.
Ceramides and sphingoid long-chain bases (LCBs) are precursors to more complex sphingolipids and play distinct signaling roles crucial for cell growth and survival. Conserved reactions within the sphingolipid biosynthetic pathway are responsible for the formation of these intermediates. Components of target of rapamycin complex 2 (TORC2) have been implicated in the biosynthesis of sphingolipids in S. cerevisiae; however, the precise step regulated by this complex remains unknown. Here we demonstrate that yeast cells deficient in TORC2 activity are impaired for de novo ceramide biosynthesis both in vivo and in vitro. We find that TORC2 regulates this step in part by activating the AGC kinase Ypk2 and that this step is antagonized by the Ca2+/calmodulin-dependent phosphatase calcineurin. Because Ypk2 is activated independently by LCBs, the direct precursors to ceramides, our data suggest a model wherein TORC2 signaling is coupled with LCB levels to control Ypk2 activity and, ultimately, regulate ceramide formation.
神经酰胺和鞘氨醇长链碱（LCBs）是更复杂鞘脂的前体，在细胞生长和存活中发挥着独特的关键信号作用。鞘脂生物合成途径中的保守反应负责这些中间体的形成。雷帕霉素复合物2（TORC2）的靶点成分已被证明参与酿酒酵母中鞘脂的生物合成；然而，该复合物调节的确切步骤仍不清楚。在这里，我们证明缺乏TORC2活性的酵母细胞在体内和体外从头合成神经酰胺的过程中均受到损害。我们发现TORC2部分通过激活AGC激酶Ypk2来调节这一步骤，并且这一步骤受到Ca2+/钙调蛋白依赖性磷酸酶钙调神经磷酸酶的拮抗。由于Ypk2由神经酰胺的直接前体LCBs独立激活，我们的数据提出了一个模型，其中TORC2信号与LCB水平耦合以控制Ypk2活性，并最终调节神经酰胺的形成。
