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PMID: 9351830 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Inhibition of NF-kappa-B cellular function via specific targeting of the I-kappa-B-ubiquitin ligase.

The EMBO journal ·Vol. 16 ·No. 21 ·1997-11-03 ·Pages 6486-94

Yaron A, Gonen H, Alkalay I, Hatzubai A, Jung S, Beyth S, Mercurio F, Manning AM, Ciechanover A, Ben-Neriah Y

Abstract

Activation of the transcription factor NF-kappa B is a paradigm for signal transduction through the ubiquitin-proteasome pathway: ubiquitin-dependent degradation of the transcriptional inhibitor I kappa B in response to cell stimulation. A major issue in this context is the nature of the recognition signal and the targeting enzyme involved in the proteolytic process. Here we show that following a stimulus-dependent phosphorylation, and while associated with NF-kappa B, I kappa B is targeted by a specific ubiquitin-ligase via direct recognition of the signal-dependent phosphorylation site; phosphopeptides corresponding to this site specifically inhibit ubiquitin conjugation of I kappa B and its subsequent degradation. The ligase recognition signal is functionally conserved between I kappa B alpha and I kappa B beta, and does not involve the nearby ubiquitination site. Microinjection of the inhibitory peptides into stimulated cells abolished NF-kappa B activation in response to TNF alpha and the consequent expression of E-selectin, an NF-kappa B-dependent cell-adhesion molecule. Inhibition of NF-kappa B function by specific blocking of ubiquitin ligase activity provides a novel approach for intervening in cellular processes via regulation of unique proteolytic events.

MeSH Terms
Amino Acid Sequence Biological Transport Cell Nucleus/metabolism Cells, Cultured Cysteine Endopeptidases/metabolism Cytoplasm/metabolism E-Selectin/biosynthesis,genetics Endothelium, Vascular/drug effects,metabolism HeLa Cells/drug effects,metabolism Humans Jurkat Cells/drug effects,metabolism Ligases/antagonists & inhibitors,physiology Molecular Sequence Data Multienzyme Complexes/metabolism NF-kappa B/antagonists & inhibitors Peptide Fragments/pharmacology Phosphorylation/drug effects Proteasome Endopeptidase Complex Protein Processing, Post-Translational/drug effects Proto-Oncogene Proteins/metabolism Signal Transduction/drug effects,physiology Transcription Factor RelB Transcription Factors Transcription, Genetic/drug effects Ubiquitin-Protein Ligases Ubiquitins/metabolism Umbilical Veins
Chemicals
E-Selectin Multienzyme Complexes NF-kappa B Peptide Fragments Proto-Oncogene Proteins RELB protein, human Transcription Factors Ubiquitins Transcription Factor RelB Ubiquitin-Protein Ligases Cysteine Endopeptidases Proteasome Endopeptidase Complex Ligases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Yaron A
Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem.
Gonen H
Alkalay I
Hatzubai A
Jung S
Beyth S
Mercurio F
Manning A M
Ciechanover A
Ben-Neriah Y
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/16.21.6486
Published
1997-11-03
Pages
6486-94
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1170254
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/16.21.6486 PMC Full Text View journal details
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