The antioxidant machinery of the endoplasmic reticulum: Protection and signaling.
Cellular metabolism is inherently linked to the production of oxidizing by-products, including reactive oxygen species (ROS) hydrogen peroxide (H2O2). When present in excess, H2O2 can damage cellular biomolecules, but when produced in coordinated fashion, it typically serves as a mobile signaling messenger. It is therefore not surprising that cell health critically relies on both low-molecular-weight and enzymatic antioxidant components, which protect from ROS-mediated damage and shape the propagation and duration of ROS signals. This review focuses on H2O2-antioxidant cross talk in the endoplasmic reticulum (ER), which is intimately linked to the process of oxidative protein folding. ER-resident or ER-regulated sources of H2O2 and other ROS, which are subgrouped into constitutive and stimulated sources, are discussed and set into context with the diverse antioxidant mechanisms in the organelle. These include two types of peroxide-reducing enzymes, a high concentration of glutathione derived from the cytosol, and feedback-regulated thiol-disulfide switches, which negatively control the major ER oxidase ER oxidoreductin-1. Finally, new evidence highlighting emerging principles of H2O2-based cues at the ER will likely set a basis for establishing ER redox processes as a major line of future signaling research. A fundamental problem that remains to be solved is the specific, quantitative, time resolved, and targeted detection of H2O2 in the ER and in specialized ER subdomains.
Laboratoire Stress Oxydants et Cancer, CEA-Saclay, Service de Biologie Intégrative et de Génétique Moléculaire, Institut de Biologie et de Technologie de Saclay, Commissariat à l׳Energie Atomique et aux Energies Alternatives, F-91191 Gif Sur Yvette, France/Institute for Integrative Biology of the Cell (I2BC), Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France. Electronic address: agnes.delaunay-moisan@cea.fr.
Agnès
A
Delaunay-Moisan
BFG Baselland, 4142 Münchenstein, Switzerland. Electronic address: christian.appenzeller@sbl.ch.
Christian
C
Appenzeller-Herzog
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
D000975:Antioxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D005978:Glutathione
Endoplasmic reticulum; Ero1; Glutathione; H(2)O(2); NADPH oxidase; Oxidative folding; PDI; Redox homeostasis; Redox signaling; UPR