Distinct roles of IkappaB proteins in regulating constitutive NF-kappaB activity

Nat Cell Biol. 2005 Sep;7(9):921-3. doi: 10.1038/ncb1296.


The inhibitor of NF-kappaB (IkappaB) family of proteins is believed to regulate NF-kappaB activity by cytoplasmic sequestration. We show that in cells depleted of IkappaBalpha, IkappaBbeta and IkappaBepsilon proteins, a small fraction of p65 binds DNA and leads to constitutive activation of NF-kappaB target genes, even without stimulation, whereas most of the p65 remains cytoplasmic. These results indicate that although IkappaBalpha, IkappaBbeta and IkappaBepsilon proteins could be dispensable for cytoplasmic retention of NF-kappaB, they are essential for preventing NF-kappaB-dependent gene expression in the basal state. We also show that in the absence of IkappaBalpha, IkappaBbeta and IkappaBepsilon proteins, cytoplasmic retention of NF-kappaB by other cellular proteins renders the pathway unresponsive to activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytoplasm / metabolism
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / physiology
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation / physiology
  • Genes, Regulator / physiology
  • I-kappa B Proteins / metabolism*
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / physiology
  • Transcription Factor RelA


  • DNA-Binding Proteins
  • I kappa B beta protein
  • I-kappa B Proteins
  • NF-kappa B
  • Nfkbia protein, mouse
  • Nfkbie protein, mouse
  • Proto-Oncogene Proteins
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • DNA