TOR signaling regulates GPCR levels on the plasma membrane and suppresses the Saccharomyces cerevisiae mating pathway

TL;DR

This study shows that TOR signaling controls GPCR levels on the cell surface in yeast, affecting mating pathway activity.

Contribution

The paper reveals a novel TOR-mediated regulation of GPCR endocytosis in yeast mating signaling.

Findings

TORC1 inhibition leads to Ste2 GPCR internalization via TORC2, Ypk1, and α-arrestins Rod1 and Rog3.

Atg8, a key autophagy protein, delivers active Ste2 receptors to the vacuole to suppress mating signaling.

TORC2 activity is essential for both ligand-dependent and ligand-independent endocytosis of Ste2.

Abstract

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 ligand-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.

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