雷帕霉素靶蛋白复合物 1（mTORC1）的 Raptor 发生 O-连接的 N-乙酰葡萄糖胺基化（O-GlcNAcylation）可传递葡萄糖信号。
O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.
机构信息
State Key Laboratory of Membrane Biology, New Cornerstone Science Laboratory, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
College of Chemistry and Molecular Engineering, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
出版信息
Mol Cell. 2023 Aug 17;83(16):3027-3040.e11. doi: 10.1016/j.molcel.2023.07.011. Epub 2023 Aug 3.
The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.
雷帕霉素复合物 1（mTORC1）的机械靶点通过响应营养水平调节代谢和细胞生长。mTORC1 的失调导致广泛的疾病。葡萄糖是细胞的主要能量供应物，因此，葡萄糖水平必须通过高度响应的信号机制准确传递给 mTORC1，以控制 mTORC1 活性。在这里，我们报告在 HEK293T 细胞中，雷帕霉素复合物 1（mTORC1）的核心组成部分 Raptor 的 O-GlcNAc 化调节葡萄糖诱导的 mTORC1 激活。从机制上讲，Raptor 上苏氨酸 700 的 O-GlcNAc 化促进了 Raptor 与 Rag GTPases 的相互作用，并促进了 mTOR 向溶酶体表面的易位，从而激活 mTORC1。此外，我们表明 AMPK 介导的 Raptor 磷酸化抑制 Raptor 的 O-GlcNAc 化并抑制 Raptor-Rags 相互作用。我们的发现揭示了一个精巧控制的机制，表明葡萄糖如何协调调节细胞的合成代谢和分解代谢。
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