Division of Biological Sciences, Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602, Japan.
Division of Biological Sciences, Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602, Japan.
Mol Cell. 2015 Jul 2;59(1):22-34. doi: 10.1016/j.molcel.2015.04.013. Epub 2015 May 14.
Despite the crucial role played by the glyoxylate cycle in the virulence of pathogens, seed germination in plants, and sexual development in fungi, we still have much to learn about its regulation. Here, we show that a previously uncharacterized SCF(Ucc1) ubiquitin ligase mediates proteasomal degradation of citrate synthase in the glyoxylate cycle to maintain metabolic homeostasis in glucose-grown cells. Conversely, transcription of the F box subunit Ucc1 is downregulated in C2-compound-grown cells, which require increased metabolic flux for gluconeogenesis. Moreover, in vitro analysis demonstrates that oxaloacetate regenerated through the glyoxylate cycle induces a conformational change in citrate synthase and inhibits its recognition and ubiquitination by SCF(Ucc1), suggesting the existence of an oxaloacetate-dependent positive feedback loop that stabilizes citrate synthase. We propose that SCF(Ucc1)-mediated regulation of citrate synthase acts as a metabolic switch for the glyoxylate cycle in response to changes in carbon source, thereby ensuring metabolic versatility and flexibility.
尽管乙醛酸循环在病原体的毒力、植物种子的萌发和真菌的有性发育中起着至关重要的作用，但我们仍然需要更多地了解其调控机制。在这里，我们发现一个以前未被描述的 SCF(Ucc1)泛素连接酶介导乙醛酸循环中的柠檬酸合酶的蛋白酶体降解，以维持葡萄糖生长细胞中的代谢稳态。相反，在 C2 化合物生长的细胞中，F 框亚基 Ucc1 的转录水平下调，这些细胞需要增加代谢通量来进行糖异生。此外，体外分析表明，通过乙醛酸循环再生的草酰乙酸诱导柠檬酸合酶发生构象变化，并抑制其被 SCF(Ucc1)识别和泛素化，提示存在一种依赖草酰乙酸的正反馈回路，稳定柠檬酸合酶。我们提出，SCF(Ucc1)介导的柠檬酸合酶的调节作用是乙醛酸循环的代谢开关，以响应碳源的变化，从而确保代谢的多功能性和灵活性。
