Departments of Pathology & Laboratory Medicine, Neurology, and Biological Chemistry, University of California, Irvine, CA, USA.
Department of Neurology, Duke University School of Medicine, Durham, NC, USA.
Life Sci Alliance. 2023 May 23;6(8). doi: 10.26508/lsa.202201525. Print 2023 Aug.
mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here, we examined the process of MAP4K3 regulation of mTORC1 and found that MAP4K3 represses the LKB1-AMPK pathway to achieve robust mTORC1 activation. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor sirtuin-1 (SIRT1) and phosphorylates SIRT1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1-AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell.
mTORC1 是控制细胞代谢状态的关键变阻器。在 mTORC1 的各种输入中，氨基酸供应是细胞内营养状态最有效的效应物。尽管 MAP4K3 在存在氨基酸的情况下促进 mTORC1 激活的作用已得到确立，但 MAP4K3 控制 mTORC1 激活的信号通路仍不清楚。在这里，我们研究了 MAP4K3 对 mTORC1 的调节过程，发现 MAP4K3 抑制 LKB1-AMPK 途径以实现强大的 mTORC1 激活。当我们寻找 MAP4K3 和 LKB1 抑制之间的调节联系时，我们发现 MAP4K3 与主营养素调节因子 SIRT1（沉默调节蛋白 1）相互作用，并磷酸化 SIRT1 以抑制 LKB1 激活。我们的研究结果揭示了一种新的信号通路的存在，该通路将氨基酸饱足感与 MAP4K3 依赖性抑制 SIRT1 联系起来，从而使抑制性 LKB1-AMPK 途径失活，并强烈激活 mTORC1 复合物，从而决定细胞的代谢状态。
