Reduction of Glucose Uptake through Inhibition of Hexose Transporters and Enhancement of Their Endocytosis by Methylglyoxal in Saccharomyces cerevisiae

Yoshida, Aya; Wei, Dandan; Nomura, Wataru; Izawa, Shingo; Inoue, Yoshiharu

doi:10.1074/jbc.m111.322222

Cited by 33 publications

(36 citation statements)

References 63 publications

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“…In comparison, GFP-tagged Hxt2 and Hxt1 were specifically localized in the plasma membrane ( Figure 7A, bottom, and Figure 7B, ctrl), as reported previously (Yoshida et al 2012). The difference in these localizations indicates that phenothiazines do not interact only with Hxts.…”

Section: Nonmetabolizable Hexose Analogues Alleviate Tc Sensitivity Vsupporting

confidence: 85%

“…Cells with ,50% of their actin patches in the bud were considered to have a depolarized actin cytoskeleton. For the detection of phenothiazines (De Filippi et al 2007) and GFPtagged Hxts (Yoshida et al 2012), logarithmic cultures of the BY4741 strains expressing HXT1-GFP and HXT2-GFP in YPD (pH 6.0) were treated with the indicated drugs. The fluorescence signals for phenothiazine detected by UV excitation (330-385 nm) were immediately recorded before changing their colors.…”

Section: Microscopic Analysismentioning

confidence: 99%

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Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast

et al. 2016

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Action mechanisms of anesthetics remain unclear because of difficulty in explaining how structurally different anesthetics cause similar effects. In Saccharomyces cerevisiae, local anesthetics and antipsychotic phenothiazines induced responses similar to those caused by glucose starvation, and they eventually inhibited cell growth. These drugs inhibited glucose uptake, but additional glucose conferred resistance to their effects; hence, the primary action of the drugs is to cause glucose starvation. In hxt 0 strains with all hexose transporter (HXT) genes deleted, a strain harboring a single copy of HXT1 (HXT1s) was more sensitive to tetracaine than a strain harboring multiple copies (HXT1m), which indicates that quantitative reduction of HXT1 increases tetracaine sensitivity. However, additional glucose rather than the overexpression of HXT1/2 conferred tetracaine resistance to wild-type yeast; therefore, Hxts that actively transport hexoses apparently confer tetracaine resistance. Additional glucose alleviated sensitivity to local anesthetics and phenothiazines in the HXT1m strain but not the HXT1s strain; thus, the glucose-induced effects required a certain amount of Hxt1. At low concentrations, fluorescent phenothiazines were distributed in various membranes. At higher concentrations, they destroyed the membranes and thereby delocalized Hxt1-GFP from the plasma membrane, similar to local anesthetics. These results suggest that the aforementioned drugs affect various membrane targets via nonspecific interactions with membranes. However, the drugs preferentially inhibit the function of abundant Hxts, resulting in glucose starvation. When Hxts are scarce, this preference is lost, thereby mitigating the alleviation by additional glucose. These results provide a mechanism that explains how different compounds induce similar effects based on lipid theory.

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Section: Nonmetabolizable Hexose Analogues Alleviate Tc Sensitivity Vsupporting

confidence: 85%

Section: Microscopic Analysismentioning

confidence: 99%

Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast

et al. 2016

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“…However, accumulating evidence demonstrates that glycolysis and, particularly, its intermediate metabolites have multiple regulatory functions in cells. For example, the highly cytotoxic side product of glycolysis, methylglyoxal, was previously shown to covalently modify several glycolytic enzymes and to affect glucose transport by enhancing the endocytosis of the Hxt1 glucose permease in S. cerevisiae (37,38). In mammals and yeast, several metabolites such as 1,3-biphosphoglycerate, phosphoenolpyruvate, and fructose-1,6-biphosphate were shown to exert feedback control on glycolysis by affecting the activity of different glycolytic enzymes (39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

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

Cairey-Remonnay

Deffaud

Wésolowski-Louvel

et al. 2015

Molecular and Cellular Biology

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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...

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“…Another mechanism that could account for the role of InsPs in glucose transport and acetyl-CoA homeostasis was suggested by the finding that Plc1p negatively regulates endocytosis of hexose transporters in an Rsp5p-dependent manner (96). Rsp5p, a HECT-type ubiquitin ligase, is involved in ubiquitination of several transporters and permeases in the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Yeast Phospholipase C Is Required for Normal Acetyl-CoA Homeostasis and Global Histone Acetylation

Galdieri

Chang

Mehrotra

et al. 2013

Journal of Biological Chemistry

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Background:Glucose metabolism provides acetyl-CoA for histone acetylation. Results: Inositol polyphosphates (InsPs), produced by the phospholipase C-dependent pathway, are required for degradation of the transcriptional repressor Mth1p, expression of glucose transporters, and normal acetyl-CoA homeostasis. Conclusion: Defect in InsP synthesis results in global histone hypoacetylation and altered transcriptional regulation. Significance: InsPs affect synthesis of glucose-derived acetyl-CoA and global histone acetylation.

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Reduction of Glucose Uptake through Inhibition of Hexose Transporters and Enhancement of Their Endocytosis by Methylglyoxal in Saccharomyces cerevisiae

Cited by 33 publications

References 63 publications

Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast

Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast

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

Yeast Phospholipase C Is Required for Normal Acetyl-CoA Homeostasis and Global Histone Acetylation

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