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Crucial Role of the Amino-Terminal Tyrosine Residue 42 and the Carboxyl-Terminal PEST Domain of IκBα in NF-κB Activation by an Oxidative Stress
Open accessAbstract
Activation of transcription factor NF-κB involves the signal-dependent degradation of basally phosphorylated inhibitors such as IκBα. In response to proinflammatory cytokines or mitogens, the transduction machinery has recently been characterized, but the activation mechanism upon oxidative stress remains unknown. In the present work, we provide several lines of evidence that NF-κB activation in a T lymphocytic cell line (EL4) by hydrogen peroxide (H2O2) did not involve phosphorylation of the serine residues 32 and 36 in the amino-terminal part of IκBα. Indeed, mutation of Ser32 and Ser36 blocked IL-1β- or PMA-induced NF-κB activation, but had no effect on its activation by H2O2. Although IκBα was phosphorylated upon exposure to H2O2, tyrosine residue 42 and the C-terminal PEST (proline-glutamic acid-serine-threonine) domain played an important role. Indeed, mutation of tyrosine 42 or serine/threonine residues of the PEST domain abolished NF-κB activation by H2O2, while it had no effect on activation by IL-1β or PMA-ionomycin. This H2O2-inducible phosphorylation was not dependent on IκB kinase activation, but could involve casein kinase II, because an inhibitor of this enzyme (5,6-dichloro-1-β-d-ribofuranosyl-benzimidazole) blocks NF-κB activation. H2O2-induced IκBα phosphorylation was followed by its degradation by calpain proteases or through the proteasome. Taken together, our findings suggest that NF-κB activation by H2O2 involves a new mechanism that is totally distinct from those triggered by proinflammatory cytokines or mitogens.
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“Multiple studies have shown that H2O2-mediated NFκB activation results from phosphorylation of IκB tyrosine residues [143,144].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [143]
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“H2O2 induces activation of factor nuclear NF-κβ (the factor that controls DNA transcription), including tyrosine phosphorylation of IkB and activation of IKK [77].”
From The Role of Reactive Species on Innate Immunity (2022) · cites this paper as [77]
In the citing paper
“Exogenous application of H2O2 or induction of H2O2 release by IL1β or LPS treatment can activate NFκB in multiple cell types, including human myeloid KBM-5 cells, human epithelial-like MCF-7 cells, mouse EL-5 T-cells and macrophages [143,144,145,146].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [143]
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“However, this process does not involve the degradation of IκB, which is controlled by IκB kinase (IKK)-mediated serine phosphorylation.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [143]
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Metadata
- Authors
- Schoonbroodt, S., Ferreira, V., Best-Belpomme, M., Boelaert, J. R., Legrand-Poels, S., Korner, M., & Piette, J.
- Affiliations
- University of Liège (BE)
- Oncogenesis, Differentiation, and Signal Transduction Laboratory, Institut de Recherche sur le Cancer-Centre Nationale de la Recherche Scientifique , Villejuif ,
- Institut National de la Santé et de la Recherche Médicale, Unit 99, Hôpital Henri Mondor , Creteil ,
- AZ Sint-Jan (BE)
- Corresponding author
- Schoonbroodt, Sonia
- Piette, Jacques
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-04
- Volume
- 164
- Issue
- 8
- Pages
- 4292-4300
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1557884422
- Cited by
- 263
- References
- 66
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 9 · 2021: 9 · 2020: 13 · 2019: 6 · 2018: 9 · 2017: 7 · 2016: 5 · 2015: 7 · 2014: 7 · 2013: 13 · 2012: 10
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- ORBi (University of Liège) (submittedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- Sidaction
- Fonds De La Recherche Scientifique - FNRS
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- NF-κB activation, IκBα, PEST domain, oxidative stress, hydrogen peroxide, IκBα phosphorylation, casein kinase 2, proteasomal degradation, IκB kinase, IL-1β, PMA/ionomycin, T cells, EL4 cells
- MeSH terms
- NF-KappaB Inhibitor alpha, Animals, Calpain, Cysteine Endopeptidases, DNA, DNA-Binding Proteins, Enzyme Activation, Humans, Hydrogen Peroxide, Multienzyme Complexes, Peptide Fragments, Phosphorylation, Protein Binding, Serine, Tumor Cells, Cultured, Tyrosine, NF-kappa B, Protein Tyrosine Phosphatases, Protein Serine-Threonine Kinases, Point Mutation, Protein Structure, Tertiary, Oxidative Stress, I-kappa B Proteins, Proteasome Endopeptidase Complex, Casein Kinase II, Mice, I-kappa B Kinase, Protein Tyrosine Phosphatase, Non-Receptor Type 12
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