Control of IκB-α Proteolysis by Site-Specific, Signal-Induced Phosphorylation
Abstract
I kappa B-alpha inhibits transcription factor NF-kappa B by retaining it in the cytoplasm. Various stimuli, typically those associated with stress or pathogens, rapidly inactivate I kappa B-alpha. This liberates NF-kappa B to translocate to the nucleus and initiate transcription of genes important for the defense of the organism. Activation of NF-kappa B correlates with phosphorylation of I kappa B-alpha and requires the proteolysis of this inhibitor. When either serine-32 or serine-36 of I kappa B-alpha was mutated, the protein did not undergo signal-induced phosphorylation or degradation, and NF-kappa B could not be activated. These results suggest that phosphorylation at one or both of these residues is critical for activation of NF-kappa B.
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Inflammatory signals such as LPS, pro-inflammatory cytokines, reactive oxygen species, advanced glycation end products, and oxidized LDL cause IKKβ phosphorylation; this phosphorylates IκBα, leading to its ubiquitination and degradation, which releases NF-κB to enter the nucleus and induce pro-inflammatory genes.
“Extracellular inflammatory signals including lipopolysaccharide (LPS), pro-inflammatory cytokines, reactive oxygen species, advanced glycation end products, and oxidized low-density lipoprotein trigger the phosphorylation of IKKβ, which in turn phosphorylates IκBα for ubiquitination and degradation by proteasome [13–18].”
From Edible blue-green algae reduce the production of pro-inflammatory cytokines by inhibiting NF-κB pathway in macrophages and splenocytes (2013) · cites this paper as [21]
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- Authors
- Brown, K., Gerstberger, S., Carlson, L., Franzoso, G., & Siebenlist, U.
- Affiliations
- National Institutes of Health (US)
- Venue
- Science
- Published
- 1995-03-10
- Volume
- 267
- Issue
- 5203
- Pages
- 1485-1488
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2070853191
- Cited by
- 1,434
- References
- 18
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 6 · 2023: 9 · 2022: 11 · 2021: 12 · 2020: 14 · 2019: 15 · 2018: 10 · 2017: 21 · 2016: 26 · 2015: 21 · 2014: 23 · 2013: 25 · 2012: 33
- FWCI
- 49.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- IκBα, NF-κB activation, protein phosphorylation, transcriptional regulation
- MeSH terms
- NF-KappaB Inhibitor alpha, Amino Acid Sequence, Animals, Cell Line, DNA-Binding Proteins, Humans, Molecular Sequence Data, Mutation, Phosphorylation, T-Lymphocytes, Tetradecanoylphorbol Acetate, Transfection, Tumor Necrosis Factor-alpha, Signal Transduction, Transcriptional Activation, Ionomycin, NF-kappa B, Point Mutation, I-kappa B Proteins, Mice
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