Inhibition of NF-κB cellular function via specific targeting of the IκB-ubiquitin ligase

Avraham Yaron, Hedva Gonen, Irit Alkalay, Ada Hatzubai, Steffen Jung, Shaul Beyth, Frank Mercurio, Anthony M. Manning, Aaron Ciechanover*, Yinon Ben-Neriah

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

Abstract

Activation of the transcription factor NF-κB is a paradigm for signal transduction through the ubiquitin-proteasome pathway: ubiquitin-dependent degradation of the transcriptional inhibitor IκB 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-κB, IκB 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 IκB and its subsequent degradation. The ligase recognition signal is functionally conserved between IκBα and IκBβ, and does not involve the nearby ubiquitination site. Microinjection of the inhibitory peptides into stimulated cells abolished NF-κB activation in response to TNFα and the consequent expression of E-selectin, an NF-κB-dependent cell-adhesion molecule. Inhibition of NF-κB function by specific blocking of ubiquitin ligase activity provides a novel approach for intervening in cellular processes via regulation of unique proteolytic events.

Original languageAmerican English
Pages (from-to)6486-6494
Number of pages9
JournalEMBO Journal
Volume16
Issue number21
DOIs
StatePublished - 1997

Bibliographical note

Funding Information:
We would like to convey our sincere appreciation to Dr. William Au for providing useful comments in the preparation of the manuscript. This research described herein was supported by Chulabhorn Research Institute and the Center of Excellence on Environmental Health and Toxicology under the S&T Post Graduate Education and Research Development Office (PERDO) of the Ministry of Education.

Keywords

  • Degradation
  • IκB phosphorylation
  • NF-κB
  • Ubiquitin
  • Ubiquitin ligase motif

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