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Article Dans Une Revue Antioxidants and Redox Signaling Année : 2017

Reexamining the function of glutathione in oxidative protein folding and secretion

Résumé

SIGNIFICANCE: Disturbance of glutathione metabolism is a hallmark of numerous diseases, yet glutathione functions are poorly understood. One key to this question is to consider its functional compartmentation. In the endoplasmic reticulum (ER), protein folding involves disulfide bond formation catalyzed by the thiol oxidase Ero1 and proteins from the disulfide isomerase family (PDI). GSH competes with substrates for oxidation by Ero1, but its requirement for ER oxidative protein folding is questioned. Recent Advances: Oxidative protein folding has been thoroughly dissected over the last decades, and its actors and their mode of action elucidated. Genetically-encoded GSH probes have recently provided an access to subcellular redox metabolism, including the ER. CRITICAL ISSUES: Of the few often-contradictory models of the role of GSH in the ER, the most popular suggest it serves as reducing power. Yet, as a reductant, GSH also activates Ero1, which questions how glutathione can nevertheless support protein reduction. Hence, whether glutathione operates in the ER as a reductant, an oxidant, or just as a "blank" compound mirroring ER/periplasm redox activity is a highly debated question, further stimulated by the puzzling occurrence of glutathione in the E. coli periplasmic "secretory" compartment, aside of the Dsb thiol-reducing and oxidase pathways. FUTURE DIRECTIONS: Addressing the mechanisms controlling glutathione traffic in and out the ER/periplasm and its recycling will help address glutathione function in secretion. In addition, as thioredoxin reductase was recently implicated in ER oxidative protein folding, the relative contribution of each of these two reducing pathways should now be addressed.

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hal-02191701 , version 1 (23-07-2019)

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Agnès Delaunay-Moisan, Alise Ponsero, Michel Toledano. Reexamining the function of glutathione in oxidative protein folding and secretion. Antioxidants and Redox Signaling, 2017, ⟨10.1089/ars.2017.7148⟩. ⟨hal-02191701⟩
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