Methylglyoxal, a Metabolite Derived from Glycolysis, Functions as a Signal Initiator of the High Osmolarity Glycerol-Mitogen-activated Protein Kinase Cascade and Calcineurin/Crz1-mediated Pathway in Saccharomyces cerevisiae

Laboratory of Molecular Microbiology, Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2005; 280(1):253-60. DOI: 10.1074/jbc.M408061200
Source: PubMed


Methylglyoxal (MG) is a typical 2-oxoaldehyde derived from glycolysis, although it inhibits the growth of cells in all types of organism. Hence, it has been questioned why such a toxic metabolite is synthesized via the ubiquitous energy-generating pathway. We have previously reported that expression of GLO1, coding for the major enzyme detoxifying MG, was induced by osmotic stress in a high osmolarity glycerol (HOG)-mitogen-activated protein (MAP) kinase-dependent manner in Saccharomyces cerevisiae. Here we show that MG activates the HOG-MAP kinase cascade. Two osmosensors, Sln1 and Sho1, have been identified to function upstream of the HOG-MAP kinase cascade, and we reveal that MG initiates the signal transduction to this MAP kinase cascade through the Sln1 branch. We also demonstrate that MG activates the Msn2 transcription factor. Moreover, MG activated the uptake of Ca(2+) in yeast cells, thereby stimulating the calcineurin/Crz1-mediated Ca(2+) signaling pathway. We propose that MG functions as a signal initiator in yeast.

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    • "Previous research has shown that Hog1 responds to various stresses in different fungi. In Sa. cerevisiae, Hog1 is activated in response to a variety of stress stimuli, including high osmolarity, oxidative stress, heat stress, cold stress, arsenite, methylglyoxal and weak acid stress, and contributes to the regulation of cell wall composition (Alonso-Monge et al., 2001; Bilsland et al., 2004; Brewster et al., 1993; Maeta et al., 2005; Mollapour & Piper, 2006; Panadero et al., 2006; Thorsen et al., 2006; Winkler et al., 2002). In Sc. pombe, the Sty1 pathway is activated in response to diverse stresses, such as osmotic stress, heat shock, oxidative stress, nitrogen limitation, carbon starvation , UV light, methylglyoxal, cold stress, arsenite and pressure (Degols et al., 1996; Degols & Russell, 1997; George et al., 2007; Millar et al., 1995; Rodríguez-Gabriel & Russell, 2005; Shiozaki & Russell, 1996; Soto et al., 2002; Takatsume et al., 2006). "
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    ABSTRACT: Fungal biocontrol agents have great potential in integrated pest management. However, poor efficacy and sensitivity to various adverse factors have hampered their wide application. In eukaryotic cells, Hog1 kinase plays a critical role in stress responses. In this study, MaHog1 (GenBank accession number EFY85878), encoding a member of the Hog1/Sty1/p38 MAPK family in Metarhizium acridum, was identified. Targeted gene disruption was used to analyze the role of MaHog1 in virulence and tolerance to adverse factors. Mutants with MaHog1 depletion showed increased sensitivity to high osmotic stress, high temperature and oxidative stress, and exhibited remarkable resistance to cell wall disturbing agents. These results suggest that Hog1 kinase has conserved function in regulating multistress responses among fungi, and that MaHog1 might influence cell wall biogenesis in M. acridum. Bioassays conducted with topical inoculation and intrahemocoel injection revealed that MaHog1 is required for both penetration and postpenetration development of M. acridum. MaHog1 disruption resulted in a significant reduction in virulence, likely due to the combination of a decrease in conidial germination, a reduction in appressorium formation, and a decline in growth rate in insect haemolymph, which might be caused by impairing the fungal tolerance to various stresses during infection.
    Preview · Article · Oct 2012 · Microbiology
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    • "Methyglyoxal and glyoxal inhibit yeast growth MG is a potent inhibitor of yeast growth (Aguilera and Prieto 2001; Aguilera et al. 2005; Bito et al. 1997; Inoue and Kimura 1996; Inoue et al. 1998; Maeta et al. 2005). Using a quantitative fitness assay, we quantified the growth inhibition for MG and glyoxal (Figure 1A). "
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    ABSTRACT: The accumulation of protein adducts caused by carbonyl stress (CS) is a hallmark of cellular aging and other diseases, yet the detailed cellular effects of this universal phenomena are poorly understood. An understanding of the global effects of CS will provide insight into disease mechanisms and can guide the development of therapeutics and lifestyle changes to ameliorate their effects. To identify cellular functions important for the response to carbonyl stress, multiple genome-wide genetic screens were performed using two known inducers of CS. We found that different cellular functions were required for resistance to stress induced by methylglyoxal (MG) and glyoxal (GLY). Specifically, we demonstrate the importance of macromolecule catabolism processes for resistance to MG, confirming and extending known mechanisms of MG toxicity, including modification of DNA, RNA, and proteins. Combining our results with related studies that examined the effects of ROS allowed a comprehensive view of the diverse range of cellular functions affected by both oxidative and carbonyl stress. To understand how these diverse cellular functions interact, we performed a quantitative epistasis analysis by creating multimutant strains from those individual genes required for glyoxal resistance. This analysis allowed us to define novel glyoxal-dependent genetic interactions. In summary, using multiple genome-wide approaches provides an effective approach to dissect the poorly understood effects of glyoxal in vivo. These data, observations, and comprehensive dataset provide 1) a comprehensive view of carbonyl stress, 2) a resource for future studies in other cell types, and 3) a demonstration of how inexpensive cell-based assays can identify complex gene-environment toxicities.
    Full-text · Article · Aug 2011 · G3-Genes Genomes Genetics
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    • "It reacts with cellular macromolecules (DNA, proteins) to form advanced glycation products and thereby affects the function of these molecules (Fleming et al. 2008; reviewed by Kalapos 2008; reviewed by Rabbani and Thornalley 2008). Methylglyoxal may also be involved in the generation of free radicals (reviewed by Kalapos 2008) and in cell signaling (Maeta et al. 2005). "
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    ABSTRACT: Stress tolerance is currently one of the major research topics in plant biology because of the challenges posed by changing climate and increasing demand to grow crop plants in marginal soils. Increased Zn tolerance and accumulation has been reported in tobacco expressing the glyoxalase 1-encoding gene from Brassica juncea. Previous studies in our laboratory showed some Zn tolerance-correlated differences in the levels of glyoxalase 1-like protein among accessions of Zn hyperaccumulator Thlaspi caerulescens. We have now isolated the corresponding gene (named here TcGLX1), including ca. 570bp of core and proximal promoter region. The predicted protein contains three glyoxalase 1 motifs and several putative sites for post-translational modification. In silico analysis predicted a number of cis-acting elements related to stress. The expression of TcGLX1 was not responsive to Zn. There was no correlation between the levels of TcGLX1 expression and the degrees of Zn tolerance or accumulation among T. caerulescens accessions nor was there co-segregation of TcGLX1 expression with Zn tolerance or Zn accumulation among F3 lines derived from crosses between plants from accessions with contrasting phenotypes for these properties. No phenotype was observed in an A. thaliana T-DNA insertion line for the closest A. thaliana homolog of TcGLX1, ATGLX1. These results suggest that glyoxalase 1 or at least the particular isoform studied here is not a major determinant of Zn tolerance in the Zn hyperaccumulator plant T. caerulescens. In addition, ATGLX1 is not essential for normal Zn tolerance in the non-tolerant, non-accumulator plant A. thaliana. Possible explanations for the apparent discrepancy between this and previous studies are discussed. KeywordsGlyoxalase 1–In silico analysis–Promoter– Thlaspi –Tolerance–Zn
    Full-text · Article · Jun 2011 · Planta
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