Asymmetric Signal Transduction through Paralogs That Comprise a Genetic Switch for Sugar Sensing in Saccharomyces cerevisiae

Abstract

Efficient uptake of glucose is especially critical to Saccharomyces cerevisiae because its preference to ferment this carbon source demands high flux through glycolysis. Glucose induces expression of HXT genes encoding hexose transporters through a signal generated by the Snf3 and Rgt2 glucose sensors that leads to depletion of the transcriptional regulators Mth1 and Std1. These paralogous proteins bind to Rgt1 and enable it to repress expression of HXT genes. Here we show that Mth1 and Std1 can substitute for one another and provide nearly normal regulation of their targets. However, their roles in the glucose signal transduction cascade have diverged significantly. Mth1 is the prominent effector of Rgt1 function because it is the more abundant of the two paralogs under conditions in which both are active (in the absence of glucose). Moreover, the cellular level of Mth1 is quite sensitive to the amount of available glucose. The abundance of Std1 protein, on the other hand, remains essentially constant over a similar range of glucose concentrations. The signal generated by low levels of glucose is amplified by rapid depletion of Mth1; the velocity of this depletion is dependent on both its rate of degradation and swift repression of MTH1 transcription by the Snf1-Mig1 glucose repression pathway. Quantitation of the contributions of Mth1 and Std1 to regulation of HXT expression reveals the unique roles played by each paralog in integrating nutrient availability with metabolic capacity: Mth1 is the primary regulator; Std1 serves to buffer the response to glucose.

A quantitative model of glucose signaling in yeast reveals an incoherent feed forward loop leading to a specific, transient pulse of transcription

“…Among maximal transcription rates, each HXT gene was significantly affected only by its own rate, and even then the effects were much smaller than those involving MTH1. Together, these observations point to MTH1 as the keystone of the system (22). In general, MIG2 is also more significant than MIG1.…”

Improvement of Glucose Uptake Rate and Production of Target Chemicals by Overexpressing Hexose Transporters and Transcriptional Activator Gcr1 in Saccharomyces cerevisiae

“…In YPD medium, derepression of HXT1 seems to have been mainly responsible for the increase in glucose uptake rate in the std1⌬ and std1⌬ mth1⌬ strains under our experimental conditions, although we cannot rule out the contributions of other Rgt1 target genes. Unexpectedly, the std1⌬ and std1⌬ mth1⌬ strains exhibited reduced expression levels of HXT2 and HXT4, which might have been due to indirect effects of derepressing other Rgt1 target genes such as MIG2, which encodes a repressor for HXT2 and HXT4 (10,35).…”

“…The effects of eliminating Mth1 and Std1 corepressors of HXT genes were more complicated due to the complex nature of the regulatory networks and the multiple targets regulated by Rgt1 (19). Mth1 and Std1 are homologous proteins acting as corepressors of Rgt1, but their cellular functions are distinguished mainly on the basis of their differential expression levels depending on glucose concentrations (35). Although expression levels of Std1 are not much affected by glucose concentrations, Mth1, whose expression is repressed by the Snf1-Mig1 glucose repression pathway, is abundant only under glucose starvation conditions (17,35,36).…”

“…Mth1 and Std1 are homologous proteins acting as corepressors of Rgt1, but their cellular functions are distinguished mainly on the basis of their differential expression levels depending on glucose concentrations (35). Although expression levels of Std1 are not much affected by glucose concentrations, Mth1, whose expression is repressed by the Snf1-Mig1 glucose repression pathway, is abundant only under glucose starvation conditions (17,35,36). The effects of dele- tion of MTH1 and/or STD1 on glucose uptake were more prominent in YPD medium than in SC medium.…”

The Filamentous Growth MAPK Pathway Responds to Glucose Starvation Through the Mig1/2 Transcriptional Repressors in Saccharomyces cerevisiae

“…Among the pathways that control the cellular response to glucose levels are the Snf3/Rgt2 pathway (Ozcan and Johnston 1999), the Ras2-cAMP-protein kinase A (PKA) pathway (Thevelein and Voordeckers 2009), and a glucose repression pathway that is regulated by the ubiquitous nutrient-sensing AMP-dependent kinase (AMPK) Snf1 (Carlson 1999). Snf3 and Rgt2 are glucose sensors that regulate the expression of hexose transporters (Hxt) of appropriate affinities through the transcriptional repressor Rgt1 (Ozcan and Johnston 1996;Sabina and Johnston 2009). Gpr1 is another glucose sensor (Nakafuku et al 1988;Kraakman et al 1999;Harashima and Heitman 2002;Peeters et al 2007;Thevelein and Voordeckers 2009) that, together with the major nutrient regulatory GTPase Ras2 (Kataoka et al 1984), converges on adenylate cyclase to regulate cellular cAMP levels and PKA activity (Toda et al 1987;Robertson and Fink 1998;Pan and Heitman 1999;Robertson et al 2000).…”