Regulation of NF-κB by ubiquitination and degradation of the IκBs

Naama Kanarek, Yinon Ben-Neriah*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

262 Scopus citations

Abstract

The nuclear factor-κB (NF-κB) signaling pathway is a busy ground for the action of the ubiquitin-proteasome system; many of the signaling steps are coordinated by protein ubiquitination. The end point of this pathway is to induce transcription, and to this end, there is a need to overcome a major obstacle, a set of inhibitors (IκBs) that bind NF-κB and prohibit either the nuclear entry or the DNA binding of the transcription factor. Two major signaling steps are required for the elimination of the inhibitors: activation of the IκB kinase (IKK) and degradation of the phosphorylated inhibitors. IKK activation and IκB degradation involve different ubiquitination modes; the latter is mediated by a specific E3 ubiquitin ligase SCF β-TrCP. The F-box component of this E3, β-TrCP, recognizes the IκB degron formed following phosphorylation by IKK and thus couples IκB phosphorylation to ubiquitination. SCF β-TrCP-mediated IκB ubiquitination and degradation is a very efficient process, often resulting in complete degradation of the key inhibitor IκBα within a few minutes of cell stimulation. In vivo ablation of β-TrCP results in accumulation of all the IκBs and complete NF-κB inhibition. As many details of IκB-β-TrCP interaction have been worked out, the development of β-TrCP inhibitors might be a feasible therapeutic approach for NF-κB-associated human disease. However, we may still need to advance our understanding of the mechanism of IκB degradation as well as of the diverse functions of β-TrCP in vivo.

Original languageAmerican English
Pages (from-to)77-94
Number of pages18
JournalImmunological Reviews
Volume246
Issue number1
DOIs
StatePublished - Mar 2012

Keywords

  • IκB degradation
  • NF-κB activation
  • Transcription regulation
  • Ubiquitin
  • β-TrCP

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