title: Redox controls UPR to control redox.
abstract: In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca(2+) efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA 19104, USA davide.laptop@gmail.com christian.appenzeller@unibas.ch.
authors.forename: Davide
authors.initials: D
authors.lastname: Eletto
authors.affiliation: INSERM U1053, Université Bordeaux 33076 Segalen, Bordeaux, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yair
authors.initials: Y
authors.lastname: Argon
authors.affiliation: Division of Molecular & Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland davide.laptop@gmail.com christian.appenzeller@unibas.ch.
authors.forename: Christian
authors.initials: C
authors.lastname: Appenzeller-Herzog
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species
keywords: Endoplasmic reticulum; Endoplasmic reticulum stress; Mitochondria; Protein disulfide isomerase; Reactive oxygen species; Unfolded protein response