Phosphorylation of IκBα Precedes but Is Not Sufficient for Its Dissociation from NF-κB
Open accessAbstract
NF-kappa B is an important activator of immune and inflammatory response genes. NF-kappa B is sequestered in the cytoplasm of nonstimulated cells through interaction with the I kappa B inhibitors. These inactive complexes are dissociated in response to a variety of extracellular signals, thereby allowing free NF-kappa B dimers to translocate to the nucleus and active transcription of specific target genes. The current dogma is that phosphorylation of the I kappa Bs is responsible for dissociation of the inactive complexes, an event that is rendered irreversible by rapid I kappa B degradation. Here, we show that inducers of NF-kappa B activity stimulate the hyperphosphorylation of one of the I kappa Bs, I kappa B alpha. However, contrary to the present dogma the hyperphosphorylated form of I kappa B alpha remains associated with NF-kappa B components such as RelA (p65). Thus, phosphorylation of I kappa B alpha is not sufficient to cause dissociation of the inactive NF-kappa B:I kappa B alpha complex. However, that complex is disrupted through the selective degradation of phosphorylated I kappa B alpha in response to extracellular signals. Using a variety of protease inhibitors, some of which have specificity towards the multicatalytic proteinase complex, we demonstrate that degradation of I kappa B alpha is required for NF-kappa B activation. The results of these experiments are more consistent with a new model according to which phosphorylation of I kappa B alpha associated with NF-kappa B marks it for proteolytic degradation. I kappa B alpha is degraded while bound to NF-kappa B. The selective degradation of I kappa B alpha releases active NF-kappa B dimers which can translocate to the nucleus to activate specific target genes.
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- Authors
- DiDonato, J. A., Mercurio, F., & Karin, M.
- Affiliations
- University of California San Diego (US)
- SignalRx Pharmaceuticals (United States) (US)
- ORCID
- DiDonato, Joseph A.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1995-03-01
- Volume
- 15
- Issue
- 3
- Pages
- 1302-1311
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC230353
- OpenAlex
- W2169053713
- Cited by
- 337
- References
- 63
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 4 · 2017: 5 · 2016: 7 · 2015: 2 · 2014: 4 · 2013: 5 · 2012: 5
- FWCI
- 18.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01ca050528-07)
- Laboratório Nacional de Luz Síncrotron
- National Heart, Lung, and Blood Institute (HL 35018, P01HL035018)
- National Cancer Institute (CA50528)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-085401)
- Lawrence Livermore National Laboratory
- 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, IκB degradation, RelA/p65, NF-κB inhibitors, proteasome, proteolysis, nuclear translocation
- MeSH terms
- NF-KappaB Inhibitor alpha, Amino Acid Sequence, Cysteine Endopeptidases, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, HeLa Cells, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Models, Biological, Molecular Sequence Data, Multienzyme Complexes, Oligopeptides, Phosphorylation, Protease Inhibitors, Transfection, Tumor Cells, Cultured, Signal Transduction, NF-kappa B, I-kappa B Proteins, Macromolecular Substances, Proteasome Endopeptidase Complex, Transcription Factor RelA
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