Arita Yuko, Nishimura Shinichi, Ishitsuka Reiko, Kishimoto Takuma, Ikenouchi Junichi, Ishii Kumiko, Umeda Masato, Matsunaga Shigeki, Kobayashi Toshihide, Yoshida Minoru
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
Chem Biol. 2015 May 21;22(5):604-10. doi: 10.1016/j.chembiol.2015.04.011. Epub 2015 May 7.
Roles of lipids in the cell membrane are poorly understood. This is partially due to the lack of methodologies, for example, tool chemicals that bind to specific membrane lipids and modulate membrane function. Theonellamides (TNMs), marine sponge-derived peptides, recognize 3β-hydroxysterols in lipid membranes and induce major morphological changes in cultured mammalian cells through as yet unknown mechanisms. Here, we show that TNMs recognize cholesterol-containing liquid-disordered domains and induce phase separation in model lipid membranes. Modulation of membrane order was also observed in living cells following treatment with TNM-A, in which cells shrank considerably in a cholesterol-, cytoskeleton-, and energy-dependent manner. These findings present a previously unrecognized mode of action of membrane-targeting natural products. Meanwhile, we demonstrated the importance of membrane order, which is maintained by cholesterol, for proper cell morphogenesis.
脂质在细胞膜中的作用尚不清楚。部分原因是缺乏相关方法，例如，缺乏能与特定膜脂结合并调节膜功能的工具化学物质。西奥内拉酰胺（TNMs）是源自海洋海绵的肽，可识别脂质膜中的3β-羟基甾醇，并通过尚未明确的机制在培养的哺乳动物细胞中诱导主要的形态变化。在这里，我们表明TNMs识别含胆固醇的液态无序结构域并在模型脂质膜中诱导相分离。在用TNM-A处理后的活细胞中也观察到了膜有序性的调节，其中细胞以胆固醇、细胞骨架和能量依赖的方式显著收缩。这些发现揭示了一种以前未被认识的膜靶向天然产物的作用模式。同时，我们证明了由胆固醇维持的膜有序性对细胞正常形态发生的重要性。
