Hepowit Nathaniel L, Singkhek Hayley L, Johnson Derek J, MacGurn Jason A
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States.
bioRxiv. 2025 May 14:2025.05.12.653625. doi: 10.1101/2025.05.12.653625.
Cell growth checkpoints require coordination between multiple sensing and signaling systems to ensure that cells only proceed with growth and division when conditions are favorable and adequate resources are available. This coordination between nutrient sensing and growth signaling is fundamental to understanding how nutrient supply regulates the cellular metabolic economy. Much of our current understanding is driven by studies that examine the cellular response to nutrient deprivation. For example, TORC1 activity promotes cell growth when amino acids are available, but amino acid deprivation decreases TORC1 activity resulting in activation of catabolic activities. In this study, we examine how cells respond to stimulation with excess amino acids. We report that stimulation with excess Ile, Phe and Met slows cell growth and triggers a G1 cell cycle arrest. Similar to a starvation response, surplus Ile, Phe and Met induce autophagy and trigger decreased TORC1 activity. In the case of stimulation with excess Met, the Gcn2 pathway is required for growth arrest, autophagy induction, and TORC1 dampening. Unexpectedly, Gcn2 is activated by stimulation with excess Met, and this activation requires endocytosis of the methionine transporter Mup1. These results indicate that endocytosis of an amino acid transporter is required to activate the Gcn2 pathway, providing an example for how nutrient transporter trafficking may function as a sensor contributing to cell growth control.
细胞生长检查点需要多个传感和信号系统之间的协调，以确保细胞仅在条件有利且有足够资源可用时才进行生长和分裂。营养传感与生长信号之间的这种协调对于理解营养供应如何调节细胞代谢经济至关重要。我们目前的许多理解是由研究细胞对营养剥夺的反应所驱动的。例如，当有氨基酸时，TORC1活性促进细胞生长，但氨基酸剥夺会降低TORC1活性，从而导致分解代谢活动的激活。在这项研究中，我们研究细胞如何对过量氨基酸的刺激做出反应。我们报告说，用过量的异亮氨酸、苯丙氨酸和甲硫氨酸刺激会减缓细胞生长并引发G1期细胞周期停滞。与饥饿反应类似，过量的异亮氨酸、苯丙氨酸和甲硫氨酸会诱导自噬并引发TORC1活性降低。在用过量甲硫氨酸刺激的情况下，生长停滞、自噬诱导和TORC1抑制需要Gcn2途径。出乎意料的是，Gcn2被过量甲硫氨酸刺激激活，这种激活需要甲硫氨酸转运蛋白Mup1的内吞作用。这些结果表明，氨基酸转运蛋白的内吞作用是激活Gcn2途径所必需的，为营养转运蛋白运输如何作为一种有助于细胞生长控制的传感器发挥作用提供了一个例子。
