MAPK feedback encodes a switch and timer for tunable stress adaptation in yeast

Signaling pathwayscan behaveasswitchesorrheostats, generating binary orgradedresponses toa given cell stimulus. We evaluated whether a single signaling pathway can simultaneously encode a switch and a rheostat. We found that the kinase Hog1 mediated a bifurcated cellular response: Activation and commitmentto adaptation toosmotic stressare switch-like,whereas protein induction and the resolution of this commitment are graded. Through experimentation, bioinformatics analysis, and computational modeling, we determined that graded recovery is encoded through feedback phosphorylation and a gene induction program that is both temporally staggered and variable across the population. This switch-torheostat signaling mechanism represents a versatile stress adaptation system, wherein a broad range of inputs generate an “all-in” response that is later tuned to allow graded recovery of individual cells over time.