Leclerc Nicholas R, Dunne Toby M, Shrestha Sudati, Johnson Cory P, Kelley Joshua B
Department of Molecular and Biomedical Sciences, University of Maine; Orono ME, USA.
Graduate School of Biomedical Science and Engineering, University of Maine; Orono ME, USA.
bioRxiv. 2025 Apr 5:2024.05.09.593412. doi: 10.1101/2024.05.09.593412.
Target of Rapamycin (TOR) complexes and G-protein-coupled receptors (GPCRs) are crucial signaling hubs that coordinate adaptive responses to environmental inputs. While GPCR-mediated regulation of TOR has been extensively studied, little is known about TOR-mediated regulation of GPCRs. Here, we establish TOR as a regulator of GPCR signaling via its control of receptor endocytosis in the yeast mating system. By pairing fluorescence microscopy with yeast genetic approaches, we identify the machinery that bridges TOR nutrient sensing to GPCR internalization. Furthermore, we find that autophagic machinery is employed during mating to deliver active receptor to the vacuole (lysosome), suppressing the mating pathway. These results demonstrate that TOR regulates the localization and signaling of the yeast mating GPCR in both ligand-dependent and -independent contexts. These pathways are highly conserved, suggesting that TOR-regulation of GPCRs may be a broadly conserved mechanism for integrating competing signals involving metabolic state and external communications.
雷帕霉素靶蛋白（TOR）复合物和G蛋白偶联受体（GPCR）是协调对环境输入的适应性反应的关键信号枢纽。虽然GPCR介导的TOR调节已得到广泛研究，但关于TOR介导的GPCR调节却知之甚少。在这里，我们通过在酵母交配系统中控制受体内吞作用，确立了TOR作为GPCR信号传导的调节因子。通过将荧光显微镜与酵母遗传学方法相结合，我们确定了将TOR营养感知与GPCR内化联系起来的机制。此外，我们发现交配过程中利用自噬机制将活性受体递送至液泡（溶酶体），从而抑制交配途径。这些结果表明，TOR在依赖配体和不依赖配体的情况下均调节酵母交配GPCR的定位和信号传导。这些途径高度保守，这表明TOR对GPCR的调节可能是一种广泛保守的机制，用于整合涉及代谢状态和外部通讯的竞争性信号。
