The mechanistic target of rapamycin complex 1 (mTORC1) kinase regulates cell growth by setting the balance between anabolic and catabolic processes. To be active, mTORC1 requires the environmental presence of amino acids and glucose. While a mechanistic understanding of amino acid sensing by mTORC1 is emerging, how glucose activates mTORC1 remains mysterious. Here, we used metabolically engineered human cells lacking the canonical energy sensor AMP-activated protein kinase to identify glucose-derived metabolites required to activate mTORC1 independent of energetic stress. We show that mTORC1 senses a metabolite downstream of the aldolase and upstream of the GAPDH-catalysed steps of glycolysis and pinpoint dihydroxyacetone phosphate (DHAP) as the key molecule. In cells expressing a triose kinase, the synthesis of DHAP from DHA is sufficient to activate mTORC1 even in the absence of glucose. DHAP is a precursor for lipid synthesis, a process under the control of mTORC1, which provides a potential rationale for the sensing of DHAP by mTORC1.

雷帕霉素复合物 1 (mTORC1) 激酶的机制靶标通过设定合成代谢和分解代谢过程之间的平衡来调节细胞生长。为了发挥活性，mTORC1 需要环境中存在氨基酸和葡萄糖。虽然 mTORC1 对氨基酸感应的机制正在逐渐形成，但葡萄糖如何激活 mTORC1 仍然是个谜。在这里，我们使用缺乏典型能量传感器 AMP 激活蛋白激酶的代谢工程人类细胞来识别独立于能量应激激活 mTORC1 所需的葡萄糖衍生代谢物。我们发现，mTORC1 能够感知醛缩酶下游和 GAPDH 催化的糖酵解步骤上游的代谢物，并精确定位磷酸二羟丙酮 (DHAP) 作为关键分子。在表达丙糖激酶的细胞中，即使在没有葡萄糖的情况下，从 DHA 合成 DHAP 也足以激活 mTORC1。 DHAP 是脂质合成的前体，脂质合成是 mTORC1 控制下的过程，这为 mTORC1 感知 DHAP 提供了潜在的原理。