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Dynamic redox control of NF-κB through glutaredoxin-regulated S-glutathionylation of inhibitory κB kinase β
Open accessAbstract
The transcription factor NF-κB, a central regulator of immunity, is subject to regulation by redox changes. We now report that cysteine-179 of the inhibitory κB kinase (IKK) β-subunit of the IKK signalosome is a central target for oxidative inactivation by means of S-glutathionylation. S-glutathionylation of IKK-β Cys-179 is reversed by glutaredoxin (GRX), which restores kinase activity. Conversely, GRX1 knockdown sensitizes cells to oxidative inactivation of IKK-β and dampens TNF-α-induced IKK and NF-κB activation. Primary tracheal epithelial cells from Glrx1 -deficient mice display reduced NF-κB DNA binding, RelA nuclear translocation, and MIP-2 (macrophage inflammatory protein 2) and keratinocyte-derived chemokine production in response to LPS. Collectively, these findings demonstrate the physiological relevance of the S-glutathionylation–GRX redox module in controlling the magnitude of activation of the NF-κB pathway.
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“In addition, I-κB-Kinase (IKK) complex is the core component of NF-κB and is a target of ROS, affecting thus NF-κB and S-glutathionylation and inhibited IKKβ activity (Reynaert et al. 2006).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Reynaert et al. 2006
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Cites
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Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD
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Crosstalk of reactive oxygen species and NF-κB signaling
Morgan, M. J., & Liu, Z.-G. (2011) · Cell Research · doi:10.1038/cr.2010.178 · Cited by 3,505
Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging
Jomova, K., Raptova, R., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M. (2023) · Archives of Toxicology · doi:10.1007/s00204-023-03562-9 · Cited by 2,638
Ros and ros-mediated cellular signaling
Zhang, J., Wang, X., Vikash, V., Ye, Q., Wu, D., Liu, Y., & Dong, W. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/4350965 · Cited by 1,980
Redox regulation of cell survival
Trachootham, D., Lu, W., Ogasawara, M. A., Valle, N. R.-D., & Huang, P. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1957 · Cited by 1,781
Redox metabolism: ROS as specific molecular regulators of cell signaling and function
Lennicke, C., & Cochemé, H. M. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.018 · Cited by 1,313
Metadata
- Authors
- Reynaert, N. L., van der Vliet, A., Guala, A. S., McGovern, T., Hristova, M., Pantano, C., Heintz, N. H., Heim, J., Ho, Y.-S., Matthews, D. E., Wouters, E. F. M., & Janssen-Heininger, Y. M. W.
- Affiliations
- Maastricht University (NL)
- Departments of *Pathology and
- University of Vermont (US)
- Wayne State University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-08-29
- Volume
- 103
- Issue
- 35
- Pages
- 13086-13091
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1559757
- OpenAlex
- W2166902551
- Cited by
- 442
- References
- 37
- Citations by year
- 2026: 19 · 2025: 12 · 2024: 19 · 2023: 19 · 2022: 18 · 2021: 20 · 2020: 23 · 2019: 23 · 2018: 13 · 2017: 25 · 2016: 18 · 2015: 24 · 2014: 22 · 2013: 28 · 2012: 29
- FWCI
- 9.51
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (P20 RL15557)
- U.S. Public Health Service (P20 RL-15557)
- National Heart, Lung, and Blood Institute (R01 HL60014, P01 HL074295, R01HL074295, R01HL060812, R01HL060014, HL 60812)
- National Center for Research Resources (P20RR015557)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- NF-κB, S-glutathionylation, glutaredoxin, redox regulation, oxidative inactivation, TNF signaling, tracheal epithelial cells, lipopolysaccharide response, chemokine production, p65 nuclear translocation
- MeSH terms
- Animals, Cells, Cultured, Cysteine, Glutathione, Hydrogen Peroxide, Lipopolysaccharides, Mice, Inbred C57BL, Oxidation-Reduction, Oxidoreductases, Respiratory System, Sulfenic Acids, Keratinocytes, Monokines, NF-kappa B, Chemokines, Protein Subunits, Mice, I-kappa B Kinase, Chemokine CXCL2, Glutaredoxins
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