Glutathione- and non-glutathione-based oxidant control in the endoplasmic reticulum

The redox-active tripeptide glutathione is an endogenous reducing agent that is found in abundance and throughout the cell. In the endoplasmic reticulum ( ER), the ratio of glutathione to glutathione disulfide is lower compared with non-secretory organelles. This relatively oxidizing thiol-disulfide milieu is essential for the oxidative folding of nascent proteins in the ER and, at least in part, maintained by the activity of ER-resident endoplasmic oxidoreductin 1 (Ero1) enzymes that oxidize cysteine side chains at the expense of molecular oxygen. Glutathione disulfide and hydrogen peroxide formed as a consequence of Ero1 activity are widely considered as being inoperative and potentially dangerous by-products of oxidative protein folding in the ER. In contrast to this common view, this Commentary highlights the importance of glutathione- and non glutathione-based homeostatic redox control mechanisms in the ER. Stability in the thiol-disulfide system that prominently includes the protein disulfide isomerases is ensured by the contribution of tightly regulated Ero1 activity, ER-resident peroxidases and the glutathione-glutathione-disulfide redox pair that acts as a potent housekeeper of redox balance. Accordingly, the widely held concept that Ero1-mediated over-oxidation in the ER constitutes a common cause of cellular demise is critically re-evaluated.