ArticleThe Journal of biological chemistry2014
Arachidonic acid induces direct interaction of the p67(phox)-Rac complex with the phagocyte oxidase Nox2, leading to superoxide production.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 43 citations in OpenAlex.
- Tetrahydrocurcumin Attenuates NaIOAntioxidants (Basel, Switzerland) · 2026Article
- From scavenger to victim: mechanism and treatment of microglial ferroptosis in white matter injury disease.Frontiers in immunology · 2026Review
- Arachidonic acid in aging: New roles for old players.Journal of advanced research · 2025Review
- Very low-density lipoprotein receptor mediates triglyceride-rich lipoprotein-induced oxidative stress and insulin resistance.American journal of physiology. Heart and circulatory physiology · 2024Article
- Decreased LPS-induced lung injury in pigs treated with a lung surfactant protein A-derived nonapeptide that inhibits peroxiredoxin 6 activity and subsequent NOX1,2 activation.American journal of physiology. Lung cellular and molecular physiology · 2024Article
- Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis.The Journal of clinical investigation · 2023Article
- Polyunsaturated Fatty Acids and Their Immunomodulatory Actions in Periodontal Disease.Nutrients · 2023Review
- Role of Oxidative Stress in Ocular Diseases: A Balancing Act.Metabolites · 2023Review
- Arachidonic acid, a clinically adverse mediator in the ovarian cancer microenvironment, impairs JAK-STAT signaling in macrophages by perturbing lipid raft structures.Molecular oncology · 2022Article
- Inhibition of MAGL activates the Keap1/Nrf2 pathway to attenuate glucocorticoid-induced osteonecrosis of the femoral head.Clinical and translational medicine · 2021Article
- Phosphoproteomics identify arachidonic-acid-regulated signal transduction pathways modulating macrophage functions with implications for ovarian cancer.Theranostics · 2021Article
- S-Nitrosylation: An Emerging Paradigm of Redox Signaling.Antioxidants (Basel, Switzerland) · 2019Review
- Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications.Pharmacology & therapeutics · 2019Review
- Arachidonic Acid Induces ARE/Nrf2-Dependent Heme Oxygenase-1 Transcription in Rat Brain Astrocytes.Molecular neurobiology · 2018Article
- Direct Activation of NADPH Oxidase 2 by 2-Deoxyribose-1-Phosphate Triggers Nuclear Factor Kappa B-Dependent Angiogenesis.Antioxidants & redox signaling · 2018Article
- Chemical Tools for Targeted Amplification of Reactive Oxygen Species in Neutrophils.Frontiers in immunology · 2018Review
- Peroxiredoxin 6 in the repair of peroxidized cell membranes and cell signaling.Archives of biochemistry and biophysics · 2017Review
- The phospholipase A2 activity of peroxiredoxin 6 modulates NADPH oxidase 2 activation via lysophosphatidic acid receptor signaling in the pulmonary endothelium and alveolar macrophages.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
- Peroxiredoxin 6 (Prdx6) supports NADPH oxidase1 (Nox1)-based superoxide generation and cell migration.Free radical biology & medicine · 2016Article
- Oxidation of heat shock protein 60 and protein disulfide isomerase activates ERK and migration of human hepatocellular carcinoma HepG2.Oncotarget · 2016Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The phagocyte NADPH oxidase Nox2, heterodimerized with p22(phox) in the membrane, is dormant in resting cells but becomes activated upon cell stimulation to produce superoxide, a precursor of microbicidal oxidants. Nox2 activation requires two switches to be turned on simultaneously: a conformational change of the cytosolic protein p47(phox) and GDP/GTP exchange on the small GTPase Rac. These proteins, in an active form, bind to their respective targets, p22(phox) and p67(phox), leading to productive oxidase assembly at the membrane. Although arachidonic acid (AA) efficiently activates Nox2 both in vivo and in vitro, the mechanism has not been fully understood, except that AA induces p47(phox) conformational change. Here we show that AA elicits GDP-to-GTP exchange on Rac at the cellular level, consistent with its role as a potent Nox2 activator. However, even when constitutively active forms of p47(phox) and Rac1 are both expressed in HeLa cells, superoxide production by Nox2 is scarcely induced in the absence of AA. These active proteins also fail to effectively activate Nox2 in a cell-free reconstituted system without AA. Without affecting Rac-GTP binding to p67(phox), AA induces the direct interaction of Rac-GTP-bound p67(phox) with the C-terminal cytosolic region of Nox2. p67(phox)-Rac-Nox2 assembly and superoxide production are both abrogated by alanine substitution for Tyr-198, Leu-199, and Val-204 in the p67(phox) activation domain that localizes the C-terminal to the Rac-binding domain. Thus the "third" switch (AA-inducible interaction of p67(phox)·Rac-GTP with Nox2) is required to be turned on at the same time for Nox2 activation.
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