ArticleThe EMBO journal2016
Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α-mediated stress signaling.
Article in The EMBO journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 115 citations in OpenAlex.
- TIGAR overexpression alleviates intracerebral hemorrhage injury in mice by suppressing ATF4/NOX4/p22phox-mediated oxidative stress and inflammation.Acta pharmacologica Sinica · 2026Article
- A functional map of phosphoprotein phosphatase regulation identifies an evolutionarily conserved reductase for the catalytic metal ions.Nature communications · 2026Article
- Modulating Protein Function through Genetically Encoded Oxidative Chemistry.Journal of the American Chemical Society · 2026Article
- Flavonoids as Nutraceuticals to Treat Inflammatory Diseases: Focusing on Quercetin, Kaempferol, Luteolin, Apigenin, Epicatechin and Their Effects on Hepatic, Nervous, and Pulmonary Systems.Foods (Basel, Switzerland) · 2026Review
- Post-translational modifications of mitochondrion-related proteins: integrative orchestrators of cell fate networks in cardiovascular disease.Cell communication and signaling : CCS · 2026Review
- Phosphatases in tumor cell immune escape: a perspective based on the camouflage, coercion, cytoprotection.Frontiers in cell and developmental biology · 2026Review
- Comparative analysis of curcuminoid content, antioxidant capacity, and target-specific molecular docking of turmeric extracts sourced from Thailand.Food chemistry. Molecular sciences · 2025Article
- Genetic and Pharmacological Inhibition of NOX4 Protects Against Rhabdomyolysis-Induced Acute Kidney Injury Through Suppression of Endoplasmic Reticulum Stress.Antioxidants (Basel, Switzerland) · 2025Article
- The Dual Role of NOX4 in Cardiovascular Diseases: Driver of Oxidative Stress and Mediator of Adaptive Remodeling.Antioxidants (Basel, Switzerland) · 2025Review
- Variants in Nucleotide Sequences; Gene Expression; and Hematological, Immune, and Antioxidant Biomarkers Linked to Pneumonia Risk in Holstein Calves.Veterinary sciences · 2025Article
- Reactive oxygen species in hypertension.Nature reviews. Cardiology · 2025Review
- Facts, Dogmas, and Unknowns About Mitochondrial Reactive Oxygen Species in Cancer.Antioxidants (Basel, Switzerland) · 2024Review
- Cellular and molecular roles of reactive oxygen species in wound healing.Communications biology · 2024Review
- Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress.Scientific reports · 2024Article
- Mammalian integrated stress responses in stressed organelles and their functions.Acta pharmacologica Sinica · 2024Review
- Autophagy caused by oxidative stress promotes TGF-β1-induced epithelial-to-mesenchymal transition in human peritoneal mesothelial cells.Cell death & disease · 2024Article
- Exosomal miR-129 and miR-342 derived from intermittent hypoxia-stimulated vascular smooth muscle cells inhibit the eIF2α/ATF4 axis from preventing calcified aortic valvular disease.Journal of cell communication and signaling · 2023Article
- Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection.Redox biology · 2023Review
- Melatonin Mitigates iNOS-Related Effects of HEMA and Camphorquinone in Human Dental Pulp Cells: Relevance for Postoperative Sensitivity Mechanism in Type 2 Diabetes.International journal of molecular sciences · 2023Article
- The regulation of cardiac intermediary metabolism by NADPH oxidases.Cardiovascular research · 2023Review
1 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 5 institutions in 4 countries.
Funding
Abstract
Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine-threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species-generating NADPH oxidase-4 (Nox4) is induced downstream of ATF4, binds to a PP1-targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4-regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia-reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4-GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2α phosphorylation to protect tissues under stress.
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