Takayama Chihiro, Koga Ayano, Sakamoto Risa, Arita Nobuaki, Tani Motohiro
Department of Chemistry, Faculty of Sciences, Kyushu University, 744, Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
Department of Chemistry, Faculty of Sciences, Kyushu University, 744, Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
Biochem Biophys Res Commun. 2022 May 21;605:63-69. doi: 10.1016/j.bbrc.2022.03.061. Epub 2022 Mar 14.
Sphingoid long-chain bases are essential intermediates of ceramides and complex sphingolipids, and function in the regulation of various signal transduction systems. Previously, we found that, in budding yeast, intracellularly accumulated dihydrosphingosine (DHS) causes mitochondrial reactive-oxygen species (ROS)-mediated cytotoxicity, which is much stronger than phytosphingosine. In this study, we screened for suppressor mutations that confer resistance to DHS, and identified RTG2, which encodes upregulation of the mitochondrial retrograde signaling pathway (RTG pathway). Deletion of RTG3 encoding transcriptional factor for the RTG pathway suppressed the cytotoxicity of DHS, whereas deletion of MKS1 or point mutation of LST8, both of which cause increased activity of the RTG pathway, enhanced the cytotoxicity. Moreover, the deletion of RTG3 also suppressed the DHS-induced increases in ROS levels. Finally, it was found that the RTG pathway is activated on DHS treatment. These results suggested that the cytotoxicity of DHS is partially mediated through activation of the RTG pathway.
鞘氨醇长链碱是神经酰胺和复杂鞘脂的重要中间体，并在各种信号转导系统的调节中发挥作用。此前，我们发现，在出芽酵母中，细胞内积累的二氢鞘氨醇（DHS）会导致线粒体活性氧（ROS）介导的细胞毒性，这种毒性比植物鞘氨醇强得多。在本研究中，我们筛选了赋予对DHS抗性的抑制突变，并鉴定出RTG2，它编码线粒体逆行信号通路（RTG通路）的上调。编码RTG通路转录因子的RTG3缺失可抑制DHS的细胞毒性，而导致RTG通路活性增加的MKS1缺失或LST8点突变则增强了细胞毒性。此外，RTG3的缺失也抑制了DHS诱导的ROS水平升高。最后，发现RTG通路在DHS处理时被激活。这些结果表明，DHS的细胞毒性部分是通过RTG通路的激活介导的。
