Fus3 generates negative feedback that improves information transmission in yeast pheromone response

Haploid Saccharomyces cerevisiae yeast cells use a prototypic cell signaling system to transmit information about the extracellular concentration of mating pheromone secreted by potential mating partners. The ability for cells to respond distinguishably to different pheromone concentrations depends on how much information about pheromone concentration the system can transmit. Here we show that the MAPK Fus3 mediates fast-acting negative feedback that adjusts the dose-response of downstream system response to match that of receptor-ligand binding. This “dose-response alignment”, defined by a linear relationship between receptor occupancy and downstream response, can improve the fidelity of information transmission by making downstream responses corresponding to different receptor occupancies more distinguishable and reducing amplification of stochastic noise during signal transmission. We also show that one target of the feedback is a novel signal-promoting function of the RGS protein Sst2. Our work suggests that negative feedback is a general mechanism used in signaling systems to align dose-responses and thereby increase the fidelity of information transmission.