Spatiotemporal Feedforward between PKM2 Tetramers and mTORC1 Prompts mTORC1 Activation

Most mammalian cells couple glucose availability to anabolic processes via the mTORC1 pathway. However, the mechanism by which fluctuations in glucose availability are rapidly translated into mTORC1 signals remains elusive. Here, we show that cells rapidly respond to changes in glucose availability through the spatial coupling of mTORC1 and tetramers of the key glycolytic enzyme pyruvate kinase M2 (PKM2) on lysosomal surfaces in the late G1/S phases. The lysosomal localization of PKM2 tetramers enables rapid increases in local ATP concentrations around lysosomes to activate mTORC1, while bypassing the need to elevate global ATP levels in the entire cell. In essence, this spatial coupling establishes a feedforward loop to enable mTORC1 to rapidly sense and respond to changes in glucose availability. We further demonstrate that this mechanism ensures robust cell proliferation upon fluctuating glucose availability. Thus, we present mechanistic insights into the rapid response of the mTORC1 pathway to changes in glucose availability. The underlying mechanism may be applicable to the control of other cellular processes.绝大多数哺乳动物细胞通过哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）通路，将葡萄糖可获得性与合成代谢过程相耦联。然而，葡萄糖可获得性的波动如何被快速转化为mTORC1信号的具体机制仍未明确。本研究发现，细胞可通过在G1/S期晚期的溶酶体表面，将mTORC1与关键糖酵解酶丙酮酸激酶M2（PKM2）的四聚体进行空间耦联，从而快速响应葡萄糖可获得性的变化。PKM2四聚体的溶酶体定位，可使溶酶体周围局部ATP浓度快速升高，进而激活mTORC1，同时无需提升整个细胞内的全局ATP水平。本质而言，这种空间耦联构建了一条前馈环路，使mTORC1能够快速感知并响应葡萄糖可获得性的变化。我们还进一步证实，该机制可确保细胞在葡萄糖可获得性波动的情况下仍能实现稳定增殖。综上，本研究阐明了mTORC1通路快速响应葡萄糖可获得性变化的核心机制，为该领域提供了深入的机制性见解。该潜在机制或可推广至其他细胞过程的调控。