A protein kinase A–regulated network encodes short- and long-lived cellular memories

Cells can store memories of prior experiences to modulate their responses to subsequent stresses, as seen for the protein kinase A (PKA)–mediated general stress response in yeast, which is required for resistance against future stressful conditions. Using microfluidics and time-lapse microscopy, we quantitatively analyzed how the cellular memory of stress adaptation is encoded in single yeast cells. We found that cellular memory was biphasic. Short-lived memory was mediated by trehalose synthase and trehalose metabolism. Long-lived memory was mediated by PKA-regulated stress-responsive transcription factors and cytoplasmic messenger ribonucleoprotein granules. Short- and long-lived memory could be selectively induced by different priming input dynamics. Computational modeling revealed how the PKA-mediated regulatory network could encode previous stimuli into memories with distinct dynamics. This biphasic memory-encoding scheme might represent a general strategy to prepare for future challenges in rapidly changing environments.