Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Biotechnologisches Zentrum, Technische Universität Dresden, Dresden, Germany.
EMBO J. 2020 Nov 2;39(21):e101767. doi: 10.15252/embj.2019101767. Epub 2020 Oct 6.
Changes in cell metabolism and plasma membrane potential have been linked to shifts between tissue growth and differentiation, and to developmental patterning. How such changes mediate these effects is poorly understood. Here, we use the developing wing of Drosophila to investigate the interplay between cell metabolism and a key developmental regulator-the Hedgehog (Hh) signalling pathway. We show that reducing glycolysis both lowers steady-state levels of ATP and stabilizes Smoothened (Smo), the 7-pass transmembrane protein that transduces the Hh signal. As a result, the transcription factor Cubitus interruptus accumulates in its full-length, transcription activating form. We show that glycolysis is required to maintain the plasma membrane potential and that plasma membrane depolarization blocks cellular uptake of N-acylethanolamides-lipoprotein-borne Hh pathway inhibitors required for Smo destabilization. Similarly, pharmacological inhibition of glycolysis in mammalian cells induces ciliary translocation of Smo-a key step in pathway activation-in the absence of Hh. Thus, changes in cell metabolism alter Hh signalling through their effects on plasma membrane potential.
细胞代谢和质膜电位的变化与组织生长和分化的转变以及发育模式有关。这些变化如何介导这些效应还知之甚少。在这里，我们使用果蝇的发育翅膀来研究细胞代谢和关键发育调节剂——Hedgehog（Hh）信号通路之间的相互作用。我们表明，降低糖酵解会降低 ATP 的稳态水平并稳定 Smoothened（Smo），Smo 是转导 Hh 信号的 7 次跨膜蛋白。结果，转录因子 Cubitus interruptus 以全长、转录激活形式积累。我们表明糖酵解是维持质膜电位所必需的，并且质膜去极化阻止了 N-酰基乙醇酰胺的细胞摄取——脂蛋白携带的 Smo 失稳所需的 Hh 途径抑制剂。同样，在没有 Hh 的情况下，哺乳动物细胞中糖酵解的药理学抑制会诱导 Smo 的纤毛易位——这是通路激活的关键步骤。因此，细胞代谢的变化通过其对质膜电位的影响改变了 Hh 信号。
