Oxidative protein folding in the endoplasmic reticulum (ER) has emerged as a potentially significant source of cellular reactive oxygen species (ROS). Recent studies suggest that levels of ROS generated as a byproduct of oxidative folding rival those produced by mitochondrial respiration. Mechanisms that protect cells against oxidant accumulation within the ER have begun to be elucidated yet many questions still remain regarding how cells prevent oxidant-induced damage from ER folding events. Here we report a new role for a central well-characterized player in ER homeostasis as a direct sensor of ER redox imbalance. Specifically we show that a conserved cysteine in the lumenal chaperone BiP is susceptible to oxidation by peroxide, and we demonstrate that oxidation of this conserved cysteine disrupts BiP's ATPase cycle. We propose that alteration of BiP activity upon oxidation helps cells cope with disruption to oxidative folding within the ER during oxidative stress.The endoplasmic reticulum is the cellular compartment where approximately one third of the cell's proteins are made. Inside, chaperone molecules bind to newly made protein chains and help them to fold into the three-dimensional structure required for the protein to work correctly. A chaperone called Ero1 helps to facilitate this folding process by catalyzing a reaction that forms strong chemical bonds, which help stabilize the final protein structures. However, this help from Ero1 comes at a cost: forming a stabilizing bond this way also produces a peroxide molecule as a byproduct.Peroxide is a ‘reactive oxygen species’: a chemical that can oxidize and damage proteins and DNA, which can potentially kill the cell. Three other enzymes in the endoplasmic reticulum can convert peroxide into water, to protect the cells from reactive oxygen species build-up. However, not all cells that use Ero1 have these other enzymes, suggesting that other pathways must exist to manage reactive oxygen species.Wang et al. took advantage of yeast cells containing a hyperactive mutant version of the Ero1 enzyme to look for alternative detoxifying mechanisms that occur when the cell is stressed by an excess of reactive oxygen species. In these cells, Wang et al. observed that the high levels of reactive oxygen species caused part of a chaperone molecule called BiP to oxidize. This modification of BiP acts like a switch that the reactive oxygen species flip on. When activated by the reactive oxygen species, BiP enhances its activity as a folding molecular chaperone, keeping proteins apart. This is thought to allow BiP to minimize the protein misfolding that may otherwise occur in the wake of the damage caused by the building levels of peroxide. Wang et al. created a mutant BiP chaperone that mimics the oxidized form, and found that it also protects cells from the damage inflicted by the excess of reactive oxygen species.Wang et al. propose that the BiP chaperone may be an important sensor of reactive oxygen species that changes its activity when these harmful chemicals are present and helps to protect the cell from damage. The success in mimicking the protective effects of oxidized BiP with a mutant BiP suggest that in the future one may be able to design small molecule drugs that bind to BiP to produce the activity of the modified form.
Wang, J., Pareja, K. A., Kaiser, C. A., & Sevier, C. S. (2014). Redox signaling via the molecular chaperone BiP protects cells against endoplasmic reticulum-derived oxidative stress. ELife, 3. https://doi.org/10.7554/elife.03496