The production of reduced or oxidized glutathione can occur at various stages during the formation of native disulphide bonds. Protein disulphide isomerase (PDI) is used as an example of how the levels of reduced glutathione (GSH) or oxidized glutathione (GSSG) are maintained in the endoplasmic reticulum (ER). (1) Free cysteines are introduced into the ER in the form of newly translocated proteins. (2) Disulphide bonds are formed by PDI, which is reduced. PDI is oxidized by Ero1,which is oxidized by O₂, a process that generates reactive oxygen species (ROS). Detoxification of ROS can lead to an increase in GSSG. (3) PDI might also be oxidized by GSSG leading to an increase in GSH. (4) PDI is reduced by GSH, which leads to an increase in GSSG. (5) Influx and efflux of GSH or GSSG from the ER may control their ratio. Cytosolic GSSG is reduced by glutathione reductase. Similar activity might occur in the ER lumen.

PKR-like ER kinase-dependent stress response to protein misfolding in the endoplasmic reticulum of mammalian cells. The unfolded protein response in mammalian cells leads to the activation of the transmembrane kinases, Ire1α, Ire1β, PKR-like ER kinase (PERK) and the transmembrane activating transcription factor 6 (ATF6). The PERK pathway is activated after dissociation of BiP from PERK monomers, causing dimerization and activation of the cytosolic kinase domain. (Note that the role of BiP in this process is unclear (Credle et al, 2005).) This activation leads to the phosphorylation of eIF2α, causing attenuation of translation and thereby alleviating endoplasmic reticulum (ER) stress. However, translation of transcription factor ATF4 is stimulated and, with activation of NF-E2-related factor 2 (Nrf2), leads to an induction of genes involved in amino-acid synthesis. The cellular level of glutathione is increased, which can potentially protect the cell from damage caused by reactive oxygen species (ROS) produced during ER stress. Perturbation of either the PERK or ATF4 pathway leads to an increase in the production of ER-derived ROS.