Abstract
Numerous secretory and membrane proteins undergo post-translational modifications in the endoplasmic reticulum (ER), and the formation of disulfide bonds is a modification that is critical for proper protein folding. The mammalian ER contains a large family of oxidoreductases that are considered to catalyze thiol/disulfide exchange and ensure the maintenance of a redox environment within the ER. Disruption of ER homeostasis causes an accumulation of misfolded and unfolded proteins, a condition termed ER stress. Despite advances in our understanding of the ER stress response and its downstream signaling pathway, it remains unclear how ER redox balance is controlled and restored in the stressed ER. In this study, we determined that brefeldin A (BFA)-induced protein accumulation in the ER triggers reversible oxidation of transmembrane thioredoxin-related protein 1 (TMX1). Conversion of TMX1 to the oxidized state preceded the induction of immunoglobulin-binding protein, a downstream marker of ER stress. Oxidized TMX1 reverted to the basal reduced state after BFA removal, and our results suggest that glutathione is involved in maintaining TMX1 in the reduced form. These findings provide evidence for a redox imbalance caused by protein overload, and demonstrate the existence of a pathway that helps restore ER homeostasis during poststress recovery.