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 internalization of the mating GPCR, Ste2. We found that TORC1 inhibition drives internalization of Ste2 through TORC2, the kinase Ypk1, and the α-arrestins Rod1 and Rog3. Furthermore, we find that Atg8, a central player in autophagy, 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. We found that TORC2 activity is required for both rapamycin-driven and pheromone-driven endocytosis of Ste2. 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.

• PMID: 40945725
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Journal Article

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Leclerc NR, Dunne TM, Shrestha S, Johnson CP, Kelley JB

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