Glycolysis Controls Plasma Membrane Glucose Sensors To Promote Glucose Signaling in Yeasts

Abstract

Sensing of extracellular glucose is necessary for cells to adapt to glucose variation in their environment. In the respiratory yeast Kluyveromyces lactis, extracellular glucose controls the expression of major glucose permease gene RAG1 through a cascade similar to the Saccharomyces cerevisiae Snf3/Rgt2/Rgt1 glucose signaling pathway. This regulation depends also on intracellular glucose metabolism since we previously showed that glucose induction of the RAG1 gene is abolished in glycolytic mutants. Here we show that glycolysis regulates RAG1 expression through the K. lactis Rgt1 (KlRgt1) glucose signaling pathway by targeting the localization and probably the stability of Rag4, the single Snf3/Rgt2-type glucose sensor of K. lactis. Additionally, the control exerted by glycolysis on glucose signaling seems to be conserved in S. cerevisiae. This retrocontrol might prevent yeasts from unnecessary glucose transport and intracellular glucose accumulation. Sensing and adaption to environmental variations and stresses is fundamental for any cell to live and to grow properly. Among the environmental signals that cells have to consider, nutrients, and especially glucose, are of particular importance. Indeed, glucose is the principal carbon and energy source for most living organisms. Glucose signaling is a key pathway allowing cells to adapt their sugar transport system and metabolism to the quality and quantity of carbon source present in their environment.Glucose transport and the glucose signaling network have been widely studied in the fermentative yeast model Saccharomyces cerevisiae (1). The yeast Kluyveromyces lactis is an excellent alternate and complementary model organism to investigate glucose signaling (2). Indeed, the pathway is simpler, with only two glucose permeases and little if any gene redundancy. Moreover, unlike S. cerevisiae, the K. lactis living style is preferably respiratory, making it closer to superior eukaryotes. In K. lactis, the fermentative growth on medium containing 5% glucose plus antimycin A (respiration inhibitor) defines the Rag-positive (Rag ϩ ) phenotype and is informative about the functionality of glucose signaling, glucose transport, and glucose metabolism.In K. lactis, two glucose permeases are known: Rag1, with a low affinity for glucose, and Hgt1, having a high affinity for glucose (3,4). Only RAG1 expression is regulated by the extracellular glucose concentration (5). In the absence of extracellular glucose, the transcriptional repressor K. lactis Rgt1 (KlRgt1), bound to the corepressor Sms1, represses RAG1 expression (6, 7) (see Fig. 1A for a model). Extracellular glucose is sensed by the plasma membrane glucose sensor Rag4, a glucose permease homolog unable to transport glucose (8) and exhibiting a characteristic long cytoplasmic C-terminal tail thought to have a role in glucose signaling. Glucose binding to Rag4 probably leads to a conformational change allowing interaction with the casein kinase I (CKI) Rag8 (6, 9). When activated by glucose, Rag8 is supposed to phosphor...

Glucose repression can be alleviated by reducing glucose phosphorylation rate in Saccharomyces cerevisiae

“…Although the evolved mutant SR8#22 contained no alterations to the Snf3/Rgt2 glucose-sensing pathway, a reduction in the glucose consumption rate was sufficient to induce changes in transporter expression. This observation lends support to previous reports of a link between glycolytic flux and the membrane composition of sugar transporters 28 , 48 . These results indicate that the regulation by the Snf3/Rgt2 pathway on transporter expression can be superseded by a reduction in glycolytic flux.…”

“…A link between glycolytic flux and regulation of hexose transporters in yeast has been suggested 28 . Furthermore, it has been shown that xylose transport is inhibited by the presence of glucose 14 , 15 .…”

Hexokinase and Glucokinases Are Essential for Fitness and Virulence in the Pathogenic Yeast Candida albicans

“…Hence, in S. cerevisiae and K. lactis glycolytic mutants, glycolysis controls glucose signaling via the SRR pathway. The expression of several glucose-regulated genes, like hexose transporter genes, depends on a functional glycolysis, limiting therefore glucose import (Cairey-Remonnay et al, 2015). However, this control does not seem to exist in C. albicans .…”

Hexokinase and glucokinases are essential for fitness and virulence in the pathogenic yeastCandida albicans

“…Hence, in S. cerevisiae and K. lactis glycolytic mutants, glycolysis controls glucose signalling via the SRR pathway. The expression of several glucose-regulated genes, like hexose transporter genes, depends on a functional glycolysis, limiting therefore glucose import [45]. However, this control does not seem to exist in C. albicans (Fig.…”