Hyperactivity of the Ero1α Oxidase Elicits Endoplasmic Reticulum Stress but No Broad Antioxidant Response
| Autor: | Thomas Ramming, Jonas D. Schmidt, Cecilie L. Søltoft, Agnieszka S. Juncker, Esben S. Sørensen, Henning Gram Hansen, Christian Appenzeller-Herzog, Brian Christensen, Henrik Marcus Geertz-Hansen, Lars Ellgaard |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Mutation
Missense Oxidative phosphorylation Biology medicine.disease_cause Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Humans Buthionine sulfoximine Viability assay Enzyme Inhibitors Buthionine Sulfoximine Molecular Biology 030304 developmental biology Extracellular Matrix Proteins 0303 health sciences Oxidase test Membrane Glycoproteins Endoplasmic reticulum Free Radical Scavengers Cell Biology Glutathione Endoplasmic Reticulum Stress Acetylcysteine Cell biology HEK293 Cells Amino Acid Substitution chemistry Unfolded Protein Response Unfolded protein response Oxidoreductases Cell Adhesion Molecules Oxidation-Reduction 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | The Journal of biological chemistry Hansen, H G, Schmidt, J D, Søltoft, C L, Ramming, T, Geertz-Hansen, H M, Christensen, B, Sørensen, E S, Juncker, A S, Appenzeller-Herzog, C & Ellgaard, L 2012, ' Hyperactivity of the Ero1α oxidase elicits endoplasmic reticulum stress but no broad antioxidant response ', Journal of Biological Chemistry, vol. 287, no. 47, pp. 39513-39523 . https://doi.org/10.1074/jbc.M112.405050 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.405050 |
| Popis: | Oxidizing equivalents for the process of oxidative protein folding in the endoplasmic reticulum (ER) of mammalian cells are mainly provided by the Ero1α oxidase. The molecular mechanisms that regulate Ero1α activity in order to harness its oxidative power are quite well understood. However, the overall cellular response to oxidative stress generated by Ero1α in the lumen of the mammalian ER is poorly characterized. Here we investigate the effects of overexpressing a hyperactive mutant (C104A/C131A) of Ero1α. We show that Ero1α hyperactivity leads to hyperoxidation of the ER oxidoreductase ERp57 and induces expression of two established unfolded protein response (UPR) targets, BiP (immunoglobulin-binding protein) and HERP (homocysteine-induced ER protein). These effects could be reverted or aggravated by N-acetylcysteine and buthionine sulfoximine, respectively. Because both agents manipulate the cellular glutathione redox buffer, we conclude that the observed effects of Ero1α-C104A/C131A overexpression are likely caused by an oxidative perturbation of the ER glutathione redox buffer. In accordance, we show that Ero1α hyperactivity affects cell viability when cellular glutathione levels are compromised. Using microarray analysis, we demonstrate that the cell reacts to the oxidative challenge caused by Ero1α hyperactivity by turning on the UPR. Moreover, this analysis allowed the identification of two new targets of the mammalian UPR, CRELD1 and c18orf45. Interestingly, a broad antioxidant response was not induced. Our findings suggest that the hyperoxidation generated by Ero1α-C104A/C131A is addressed in the ER lumen and is unlikely to exert oxidative injury throughout the cell. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|