PT - JOURNAL ARTICLE AU - Suzannah Rutherford TI - Matters Arising: Glycerol as the actuator of integral feedback control in yeast osmotic stress signaling AID - 10.1101/045682 DP - 2016 Jan 01 TA - bioRxiv PG - 045682 4099 - http://biorxiv.org/content/early/2016/03/25/045682.short 4100 - http://biorxiv.org/content/early/2016/03/25/045682.full AB - Oudenaarden and colleagues employ elegant experiments and control theory to model perfect adaptation of the yeast osmotic stress response - the precise return of turgor pressure to its optimal, steady-state value despite variation in system parameters and the continued presence of osmotic stress. Their data convincingly show that nuclear signaling and cell volume undergo “robust perfect adaptation” implying that integral feedback must restore their steady state values. However they incorrectly map the integrator onto a minimal network that violates assumptions implicit in conventional block diagrams. Using known features of osmotic stress signaling and results presented by the authors, I argue that glycerol concentration – the integral of the rate of glycerol accumulation (synthesis versus leakage) – transforms metabolic energy into increased osmolarity that drives water influx and restoration of turgor pressure. Integral feedback control actuated through glycerol synthesis is logically positioned to provide perfect adaptation and robustness in hyperosmotic stress responses.