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Cited by 4,766NF-κB Signaling PathwaysImmune Response and InflammationSignaling Pathways in Disease

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Phosphorylation Meets Ubiquitination: The Control of NF-κB Activity

Karin, Michael, Ben-Neriah, Yinon·2000·Annual Review of Immunology
DOI 10.1146/annurev.immunol.18.1.621
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Abstract

NF-kappaB (nuclear factor-kappaB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-kappaB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression. NF-kappaB is normally sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-kappaB is controlled by a family of inhibitory proteins, IkappaBs, which bind NF-kappaB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus where it regulates gene transcription. NF-kappaB activation represents a paradigm for controlling the function of a regulatory protein via ubiquitination-dependent proteolysis, as an integral part of a phosphorylationbased signaling cascade. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. The multisubunit Ika…

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Metadata

Authors
Karin, M., & Ben-Neriah, Y.
Affiliations
  • Hebrew University of Jerusalem (IL)
  • Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction University of California, San Diego, La Jolla, California, 92093-0636;
ORCID
Karin, Michael
Venue
Annual Review of Immunology
Publisher
Annual Reviews
Published
2000-04
Volume
18
Issue
1
Pages
621-663
ISSN
  • 0732-0582 (ISSN-L)
  • 1545-3278
DOI
10.1146/annurev.immunol.18.1.621
OpenAlex
W2147921405
Cited by
4,766
References
243
Citations by year
2026: 78 · 2025: 109 · 2024: 86 · 2023: 101 · 2022: 114 · 2021: 112 · 2020: 129 · 2019: 114 · 2018: 129 · 2017: 153 · 2016: 156 · 2015: 135 · 2014: 186 · 2013: 201 · 2012: 194
FWCI
22.12
Type
journal article
Language
en
Open access
closed
Locations
  • Annual Review of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (R01 CA76188, R01CA076188)
  • National Institute of Allergy and Infectious Diseases (R01AI043477, R01 AI43477)
  • National Institute of Environmental Health Sciences (R37ES004151, R37 ES04151)
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
NF-κB, IκB phosphorylation, ubiquitination, IκB kinase, IKKα, IKKβ, E3 ubiquitin ligase, proteolysis, NF-κB nuclear translocation, TNF signaling, IL-1 signaling, Rel family transcription factors, inflammation, transcriptional regulation
MeSH terms
NF-KappaB Inhibitor alpha, Amino Acid Sequence, Animals, DNA-Binding Proteins, Humans, Molecular Sequence Data, Phosphorylation, Transcription Factors, Ubiquitins, Signal Transduction, Down-Regulation, NF-kappa B, Protein Serine-Threonine Kinases, I-kappa B Proteins, I-kappa B Kinase, NF-kappa B p50 Subunit

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