Phosphorylation meets ubiquitination: the control of NF-κB activity

Karin, Michael; Ben-Neriah, Yinon

doi:10.1146/annurev.immunol.18.1.621

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

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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NFκB is believed to play a major role in the inflammatory process.
“Because of its ability to regulate the expression of inflammatory proteins, NFκB is believed to play a major role in the inflammatory process.”
From Thymosin beta 4 suppression of corneal NFκB: A potential anti-inflammatory pathway (2007) · cites this paper as Karin and Ben-Neriah, 2000
NFκB-induced gene expression requires that NFκB becomes activated, is phosphorylated, and physically translocates from cytoplasm to the nucleus.
“NFκB-induced gene expression requires that NFκB not only becomes activated, but it must also be phosphorylated and must physically translocate from cytoplasm to the nucleus (Karin and Ben-Neriah, 2000).”
From Thymosin beta 4 suppression of corneal NFκB: A potential anti-inflammatory pathway (2007) · cites this paper as Karin and Ben-Neriah, 2000

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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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Phosphorylation meets ubiquitination: the control of NF-κB activity

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