Calico Life Sciences, LLC, South San Francisco, CA, USA.
Altos Labs, Redwood City, CA, USA.
Nat Metab. 2023 Oct;5(10):1803-1819. doi: 10.1038/s42255-023-00872-1. Epub 2023 Aug 28.
Amino acid homeostasis is critical for many cellular processes. It is well established that amino acids are compartmentalized using pH gradients generated between organelles and the cytoplasm; however, the dynamics of this partitioning has not been explored. Here we develop a highly sensitive pH reporter and find that the major amino acid storage compartment in Saccharomyces cerevisiae, the lysosome-like vacuole, alkalinizes before cell division and re-acidifies as cells divide. The vacuolar pH dynamics require the uptake of extracellular amino acids and activity of TORC1, the v-ATPase and the cycling of the vacuolar specific lipid phosphatidylinositol 3,5-bisphosphate, which is regulated by the cyclin-dependent kinase Pho85 (CDK5 in mammals). Vacuolar pH regulation enables amino acid sequestration and mobilization from the organelle, which is important for mitochondrial function, ribosome homeostasis and cell size control. Collectively, our data provide a new paradigm for the use of dynamic pH-dependent amino acid compartmentalization during cell growth/division.
氨基酸稳态对于许多细胞过程至关重要。人们已经充分认识到，使用细胞器和细胞质之间产生的 pH 梯度对氨基酸进行区室化；然而，这种分区的动态性尚未得到探索。在这里，我们开发了一种高灵敏度的 pH 报告器，并发现酿酒酵母（Saccharomyces cerevisiae）中的主要氨基酸储存隔室，即溶酶体样液泡，在细胞分裂前碱化，并在细胞分裂时重新酸化。液泡 pH 动力学需要细胞外氨基酸的摄取以及 TORC1、v-ATPase 和液泡特异性脂质磷脂酰肌醇 3,5-二磷酸的循环，这由细胞周期蛋白依赖性激酶 Pho85（哺乳动物中的 CDK5）调节。液泡 pH 的调节能够实现氨基酸的隔离和从细胞器中动员，这对于线粒体功能、核糖体稳态和细胞大小控制非常重要。总的来说，我们的数据为细胞生长/分裂过程中使用依赖 pH 的动态氨基酸区室化提供了一个新的范例。
