How to Select a Mate: Kel1 is a Phosphorylation-Regulated Suppressor of the Pheromone Signaling Pathway

Mechanisms have evolved that allow cells to detect signals and generate an appropriate response. The accuracy of these responses relies on the ability of cells to discriminate between signal and noise. How cells filter noise in signaling pathways is not well understood. We have analyzed noise suppression in the yeast pheromone signaling pathway. By combining synthetic genetic array screening, mass spectrometry and single-cell time-resolved microscopy, we discovered that the poorly characterized protein Kel1 serves as a major noise suppressor of the pathway. At the molecular level, Kel1 suppresses spontaneous activation of the pheromone response by inhibiting membrane recruitment of Ste5 and Far1. Kel1 is regulated by phosphorylation, and only the hypophosphorylated form of Kel1 suppresses signaling, reduces noise and prevents pheromone-associated cell death. Our data indicate that in response to pheromone the MAPKs Fus3 and Kss1 phosphorylate Kel1 to relieve inhibition of the pheromone pathway. Taken together, Kel1 serves as a phospho-regulated suppressor of the pheromone pathway to reduce noise, inhibit spontaneous activation of the pathway, regulate mating efficiency and to prevent pheromone-associated cell death.