Glycerol is the actuator of integral feedback control in yeast osmotic stress signaling

In a 2009 article in Cell van Oudenaarden and colleagues employed elegant experiments and control theory to model perfect adaptation of the yeast osmotic stress response – 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 showed that nuclear signaling and cell volume undergo “robust perfect adaptation” implying that integral feedback must restore their steady state values. However, the authors incorrectly mapped 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 minus leakage) – transforms metabolic energy into an increased osmolarity that drives water influx and restoration of turgor pressure. I show how integral feedback control actuated through glycerol synthesis is logically positioned to provide perfect adaptation and robustness in hyperosmotic stress responses.