Analysis of osmoadaptation system in budding yeast suggests that regulated degradation of glycerol synthesis enzyme is key to near-perfect adaptation

Abstract

In order to maintain its turgor pressure at a desired homeostatic level, budding yeast, Saccharomyces cerevisiae responds to the external variation of the osmotic pressure by varying its internal osmotic pressure through regulation of synthesis and transport of the intracellular glycerol. Hog1PP (dually phosphorylated Hog1), a final effector in the signalling pathway of the hyper osmotic stress, regulates the glycerol synthesis both at transcriptional and non-transcriptional stages. It is known that for a step-change in salt concentration leading to moderate osmotic shock, Hog1PP activity shows a transient response before it returns to the vicinity of pre-stimulus level. It is believed that an integrating process in a negative feedback loop can be a design strategy to yield such an adaptive response. Several negative feedback loops have been identified in the osmoadaptation system in yeast. However, the precise location of the integrating process in the osmoadaptation system which includes signalling, gene regulation, metabolism and biophysical modules is unclear. To address this issue, we developed a reduced model which captures various experimental observations of the osmoadaptation behaviour of wild type and mutant strains. Dynamic simulations and steady state analysis suggested that known information about the osmoadaptation system of budding yeast does not necessarily give a perfect integrating process through the known feedback loops of Hog1PP. On the other hand, regulation of glycerol synthesising enzyme degradation can result in a near integrating process leading to a near-perfect adaptation.

Implementation of integral feedback control in biological systems

“…In summary, each of the integral network motifs shown in Figure is based on (1) a negative feedback loop and (2) a zero‐order kinetic mechanism in either synthesis/activation or degradation/deactivation of the regulatory protein P. It should be noted that zero‐order kinetics is not inherent to molecular interactions but contrived through myriad ways. These include protein stabilization, incorporating a positive feedback to compensate for natural degradation, and time scale difference between the deactivation and activation mechanism . The presence of zero‐order kinetics has been hypothesized through computational studies, and a conclusive experimental validation is yet lacking.…”

“…These include protein stabilization, incorporating a positive feedback to compensate for natural degradation, and time scale difference between the deactivation and activation mechanism . The presence of zero‐order kinetics has been hypothesized through computational studies, and a conclusive experimental validation is yet lacking. Analysis of the molecular implementation of integral feedback control in biological systems is a subject of ongoing research .…”

“…The recovery of the cell volume is mediated by synthesis of intracellular osmolytes (e.g., glycerol). Figure (a) shows the osmoadaptation system network . Hog1PP (dually phosphorylated Hog1), a final effector in the signaling pathway of the hyperosmotic stress, regulates the glycerol synthesis both at the transcriptional and non‐transcriptional stages.…”

“…Patel et al developed a reduced model that captures various experimental observations of the osmoadaptation behavior of wild type and mutant strains. Dynamic simulations and steady state analysis suggest that the osmoadaptation system of budding yeast does not necessarily yield a perfect integrating process through the known feedback loops of HOG1PP . On the other hand, regulation of degradation of the glycerol‐synthesizing enzyme can result in a near integrating process and, therefore, lead to a near‐perfect adaptation (see Equation ).…”

Information processing in the adaptation of Saccharomyces cerevisiae to osmotic stress: an analysis of the phosphorelay system

“…Posas et al 1996;Hohmann 2002;Macia et al 2009;Patterson et al 2010) as well as a computational side (e.g. Klipp et al 2005;Muzzey and Ca 2009;Petelenz-Kurdziel et al 2013;Patel et al 2013). The pathway provides the cell with answers to an increased concentration of osmolytes in the environment.…”