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Deciphering the function of thiol redox control pathways, glutathione and thioredoxin: why two pathways Authors

Dr. Michel B. Toledano, Institute for Integrative Biology of the Cell (I2BC), CNRS, CEA–Saclay, Université Paris–Saclay, iBiTecS/SBIGEM, Laboratoire Stress Oxydant et Cancer, Gif-sur-Yvette, France

Location LH5, LHC

The cellular control of the redox state of the cysteine residue is carried out by the two universally conserved reductase pathways, the glutathione and thioredoxin systems. Whether, in eukaryotes, these two systems fulfil distinct functions is unknown. By exploring these pathways in S. cerevisiae, we came to the conclusion that thioredoxin take over all cellular thiol-reduction functions, which includes ribonucleotide reductase reduction, the scavenging and regulation of the stress responses to hydroperoxides, and sulfate assimilation. In fact, we never identified any processes relying on GSH for thiol reduction. To further address this question, we explored these pathways in the endoplasmic reticulum (ER), in which the folding of secreted proteins that takes place, a process requiring disulfide bond formation and reduction. The ER oxidative pathway, which catalyzes disulfide bonds formation, is made of the ER oxidase Ero1 and PDI. The ER thiol-reductive pathway is required for the isomerization of non-native disulfides, but is yet poorly characterized and requires a source of reducing power emanating from either or both thioredoxin or GSH . Indirect proofs of an ER function for either one or the other of the two thiol-reducing system have been provided, but remain controversial. We first addressed the role of the redox tripeptide GSH, and found it enters the ER by facilitated diffusion through the ER protein-conducting channel Sec61, thus providing a mechanism for the maintenance of ER GSH redox balance. We also found that an oxidized form of the chaperone Bip regulates this transport to prevent Ero1 hyperactivation by reduction. As the ER transport of GSH is activated during ER stress, we looked for a function of the tripeptide. Our data now indicate that, although totally dispensable in the unstressed ER, GSH becomes critical in the stressed ER, and reciprocally thioredoxin is important in the unstressed, but not in the stressed ER.
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