Control of IkappaBalpha proteolysis by the ubiquitin-proteasome pathway

Biochimie. Mar-Apr 2001;83(3-4):351-6. doi: 10.1016/s0300-9084(01)01237-8.


It has recently been determined that the proteolytic destruction of IkappaB (inhibitor of NF-kappaB) by the ubiquitin-proteasome system plays a key role in the immediate elimination of IkappaB from the IkappaB-(NF-kappaB) complex which allows nuclear translocation of free NF-kappaB, thus leading to activation of a multitude of target genes. The SCF(Fbw1) (composed of Skp1, Cul-1, Roc1, and Fbw1) complex, identified as an IkappaBalpha-E3 ligase, binds and ubiquitylates IkappaBalpha phosphorylated by IkappaB kinase that has been activated in response to extracellular signals. The generating poly-ubiquitin chain is finally recognized by the 26S proteasome for ultimate degradation. In this NF-kappaB signalling pathway, it becomes clear that the SCF(Fbw1) activity is enhanced by a ubiquitin-like protein NEDD8 (equivalent to Rub1) that modifies Cul-1 in a manner analogous to ubiquitylation, and consequently, IkappaBalpha proteolysis is induced. NEDD8 is a new regulator of the SCF ubiquitin-ligase, functioning as a covalent modifier for proteolytic targeting at a physiological level.

Publication types

  • Review

MeSH terms

  • Animals
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Hydrolysis
  • I-kappa B Kinase
  • I-kappa B Proteins*
  • Multienzyme Complexes / metabolism
  • NEDD8 Protein
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Peptide Hydrolases / metabolism*
  • Peptide Synthases / antagonists & inhibitors
  • Peptide Synthases / metabolism*
  • Phosphorylation
  • Proteasome Endopeptidase Complex*
  • Protein-Serine-Threonine Kinases / metabolism
  • SKP Cullin F-Box Protein Ligases
  • Signal Transduction / physiology
  • Ubiquitins / metabolism*


  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Multienzyme Complexes
  • NEDD8 Protein
  • NEDD8 protein, human
  • NF-kappa B
  • NFKBIA protein, human
  • Ubiquitins
  • NF-KappaB Inhibitor alpha
  • SKP Cullin F-Box Protein Ligases
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • Peptide Synthases