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Glycolytic enzyme GAPDH promotes peroxide stress signaling through multistep phosphorelay to a MAPK cascade

Susumu Morigasaki1, Koichi Shimada, Aminah Ikner

  • 1Department of Microbiology, College of Biological Sciences, University of California, Davis, Davis, CA 95616, USA.

Molecular Cell
|April 15, 2008
PubMed

Insights

The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) unexpectedly interacts with key proteins in the phosphorelay signaling pathway, revealing a new role for this enzyme in stress response. This interaction is crucial for transmitting environmental stress signals in yeast.

Area of Science:

  • Cellular signaling
  • Biochemistry
  • Microbiology

Background:

  • Two-component systems and phosphorelay signaling are vital for bacteria, fungi, and plants to respond to environmental stimuli.
  • In fission yeast (Schizosaccharomyces pombe), peroxide stress is mediated by a pathway involving Mak2/3 sensor kinases, Mpr1 histidine-containing phosphotransfer (HPt) protein, and Mcs4 response regulator, culminating in MAP kinase activation.

Purpose of the Study:

  • To investigate the unexpected physical association of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) with components of the phosphorelay signaling pathway in Schizosaccharomyces pombe.
  • To elucidate the role of GAPDH in transmitting peroxide stress signals.

Main Methods:

  • Co-immunoprecipitation assays to detect physical interactions between GAPDH and Mcs4.
  • Oxidation state analysis of GAPDH cysteine residues under stress conditions.
  • Genetic analysis using knockout strains to assess the necessity of Tdh1 (a GAPDH) for phosphorelay signaling.

Main Results:

  • Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was found to physically associate with the Mcs4 response regulator and stress-responsive MAP kinase kinase kinases (MAPKKKs).
  • Oxidation of Cys-152 in Tdh1 GAPDH upon H2O2 exposure enhances its binding to Mcs4.
  • Tdh1 is essential for the interaction between the Mpr1 HPt protein and Mcs4, highlighting its critical role in phosphorelay signaling.

Conclusions:

  • The glycolytic enzyme GAPDH plays a significant, previously unrecognized role in the phosphorelay signaling pathway.
  • A redox-sensitive cysteine residue in GAPDH may serve as an additional input mechanism for environmental stress signaling.

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