Cytoplasmic glutathione redox status determines survival upon exposure to the thiol-oxidant 4,4'-dipyridyl disulfide.
Dipyridyl disulfide (DPS) is a highly reactive thiol oxidant that functions as electron acceptor in thiol-disulfide exchange reactions. DPS is very toxic to yeasts, impairing growth at low micromolar concentrations. The genes TRX2 (thioredoxin), SOD1 (superoxide dismutase), GSH1 (gamma-glutamyl-cysteine synthetase) and, particularly, GLR1 (glutathione reductase) are required for survival on DPS. DPS is uniquely thiol-specific, and we found that the cellular mechanisms for DPS detoxification differ substantially from that of the commonly used thiol oxidant diamide. In contrast to this oxidant, the full antioxidant pools of glutathione (GSH) and thioredoxin are required for resistance to DPS. We found that DPS-sensitive mutants display increases in the disulfide form of GSH (GSSG) during DPS exposure that roughly correlate with their more oxidizing GSH redox potential in the cytosol and their degree of DPS sensitivity. DPS seems to induce a specific disulfide stress, where an increase in the cytoplasmic/nuclear GSSG/GSH ratio results in putative DPS target(s) becoming sensitive to DPS.
López-Mirabal
H Reynaldo
HR
Carlsberg Laboratory, Gamle Carlsberg Vej, Copenhagen Valby, Denmark.
Thorsen
Michael
M
Kielland-Brandt
Morten C
MC
Toledano
Michel B
MB
Winther
Jakob R
JR
D004220:Disulfides / Q000378:metabolism / Q000494:pharmacology*; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D016254:Mutagenesis, Insertional; D010084:Oxidation-Reduction; D010957:Plasmids / Q000235:genetics; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D018000:Receptors, Peptide / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013439:Sulfhydryl Reagents / Q000378:metabolism / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004220:Disulfides; D008565:Membrane Proteins; D011725:Pyridines; D018000:Receptors, Peptide; D029701:Saccharomyces cerevisiae Proteins; D013439:Sulfhydryl Reagents; C516110:TRX2 protein, S cerevisiae; D014157:Transcription Factors; C086677:YAP1 protein, S cerevisiae; C035560:glutathione receptor; C007542:4,4'-dipyridyl disulfide; D013879:Thioredoxins; D013482:Superoxide Dismutase; C490862:GSH1 protein, S cerevisiae; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D019803:Glutathione Disulfide