The glucose metabolite methylglyoxal inhibits expression of the glucose transporter genes by inactivating the cell surface glucose sensors Rgt2 and Snf3 in yeast

Mol Biol Cell. 2016 Mar 1;27(5):862-71. doi: 10.1091/mbc.E15-11-0789. Epub 2016 Jan 13.

Abstract

Methylglyoxal (MG) is a cytotoxic by-product of glycolysis. MG has inhibitory effect on the growth of cells ranging from microorganisms to higher eukaryotes, but its molecular targets are largely unknown. The yeast cell-surface glucose sensors Rgt2 and Snf3 function as glucose receptors that sense extracellular glucose and generate a signal for induction of expression of genes encoding glucose transporters (HXTs). Here we provide evidence that these glucose sensors are primary targets of MG in yeast. MG inhibits the growth of glucose-fermenting yeast cells by inducing endocytosis and degradation of the glucose sensors. However, the glucose sensors with mutations at their putative ubiquitin-acceptor lysine residues are resistant to MG-induced degradation. These results suggest that the glucose sensors are inactivated through ubiquitin-mediated endocytosis and degraded in the presence of MG. In addition, the inhibitory effect of MG on the glucose sensors is greatly enhanced in cells lacking Glo1, a key component of the MG detoxification system. Thus the stability of these glucose sensors seems to be critically regulated by intracellular MG levels. Taken together, these findings suggest that MG attenuates glycolysis by promoting degradation of the cell-surface glucose sensors and thus identify MG as a potential glycolytic inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endocytosis / physiology
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Gene Expression Regulation, Fungal
  • Glucose / metabolism
  • Glucose Transport Proteins, Facilitative / genetics*
  • Glucose Transport Proteins, Facilitative / metabolism
  • Lactoylglutathione Lyase / genetics
  • Lactoylglutathione Lyase / metabolism
  • Monosaccharide Transport Proteins / genetics
  • Monosaccharide Transport Proteins / metabolism*
  • Pyruvaldehyde / metabolism*
  • Pyruvaldehyde / pharmacology
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Ubiquitin-Protein Ligase Complexes / genetics
  • Ubiquitin-Protein Ligase Complexes / metabolism

Substances

  • Endosomal Sorting Complexes Required for Transport
  • Glucose Transport Proteins, Facilitative
  • HXT1 protein, S cerevisiae
  • HXT3 protein, S cerevisiae
  • Monosaccharide Transport Proteins
  • RGT2 protein, S cerevisiae
  • SNF3 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Pyruvaldehyde
  • Ubiquitin-Protein Ligase Complexes
  • Lactoylglutathione Lyase
  • RSP5 protein, S cerevisiae
  • Glucose