Cell-internal autocrine receptor inactivation supports maintenance of mating-type identity in yeast

Efficient and exclusive recognition of nonself requires quality control mechanisms to eliminate self-signaling in various types of organisms and cells. Here, we discovered a previously unknown mechanism, which inactivates self-reactive G protein–coupled receptor (GPCR) used in premating communication between the two mating types of budding yeast. Our results suggest that this mechanism of cell-internal autocrine inactivation involves receptor interaction with its cosecreted peptide ligand within the secretory pathway. We demonstrate that ligand binding elicits inactivation of the self-reactive receptor already before it reaches the cell surface. This inactivation is apparently initiated through the same pathway that is involved in the endocytic internalization and subsequent vacuolar degradation of the activated cell-surface localized receptors. We hypothesize that, beyond contributing to mating-type identity in yeast, this mechanism of proofreading may be used more generally in eukaryotic cells to suppress autocrine signaling by self-secreted peptide ligands.