Cited by 707NF-κB Signaling PathwaysImmune Response and InflammationSignaling Pathways in Disease

Mapping of the Inducible IκB Phosphorylation Sites That Signal Its Ubiquitination and Degradation†

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Didonato, Joseph, Mercurio, Frank, Rosette, Caridad, Wu-Li, Jian, Suyang, Helena, Ghosh, Sankar, Karin, Michael·1996·Molecular and Cellular Biology

Abstract

Extracellular stimuli that activate the transcription factor NF-kappaB cause rapid phosphorylation of the IkappaBalpha inhibitor, which retains NF-kappaB in the cytoplasm of nonstimulated cells. Phosphorylation of IkappaBalpha is followed by its rapid degradation, the inhibition of which prevents NF-kappaB activation. To determine the relationship between these events, we mapped the inducible phosphorylation sites of IkappaBalpha. We found that two residues, serines 32 and 36, were phosphorylated in response to either tumor necrosis factor, interleukin-1, or phorbol ester. Substitution of either serine blocks or slows down induction of IkappaBalpha degradation. Substitutions of the homologous sites in IkappaBbeta, serines 19 and 23, also prevent inducible IkappaBbeta degradation. We suggest that activation of a single IkappaB kinas e or closely related IkappaB kinases is the first cr itical step in NF-kappaB activation. Once phosphorylated, IkappaB is ubiquitinated. Unlike wild-type IkappaBalpha, the phosphorylation-defective mutants do not undergo inducible polyubiquitination. As substitution of a conserved lysine residue slows down the ubiquitination and degradation of IkappaBalpha without affecting its phosphorylation, polyubiquitination is required for inducible IkappaB degradation.

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Crossref · 10.1128/mcb.16.4.1295

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Authors
Didonato, J., Mercurio, F., Rosette, C., Wu-Li, J., Suyang, H., Ghosh, S., & Karin, M.
Affiliations
  • University of California San Diego (US)
  • Howard Hughes Medical Institute (US)
Venue
Molecular and Cellular Biology
Published
1996-04
Volume
16
Issue
4
Pages
1295-1304
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
OpenAlex
W2150033965
Cited by
707
References
51
Citations by year
2026: 1 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 11 · 2020: 12 · 2019: 9 · 2018: 2 · 2017: 9 · 2016: 9 · 2015: 7 · 2014: 18 · 2013: 12 · 2012: 13
FWCI
29.94
Type
journal article
Language
en
Open access
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p01ca050528-07)
  • National Heart, Lung, and Blood Institute (HL 35018, P01HL035018)
  • National Cancer Institute (CA50528)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
IκBα, IκBβ, NF-κB activation, phosphorylation sites, ubiquitination, protein degradation, IκB kinase, TNF-α, interleukin-1, phorbol ester, transcriptional repression
MeSH terms
NF-KappaB Inhibitor alpha, Animals, DNA-Binding Proteins, HeLa Cells, Humans, Interleukin-1, Lysine, Mutation, Peptide Mapping, Phosphorylation, Precipitin Tests, Protease Inhibitors, Serine, Tumor Necrosis Factor-alpha, Ubiquitins, NF-kappa B, 3T3 Cells, Protein Serine-Threonine Kinases, I-kappa B Proteins, Mice, I-kappa B Kinase

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