Control of NF-kappa B transcriptional activation by signal induced proteolysis of I kappa B alpha

Philos Trans R Soc Lond B Biol Sci. 1999 Sep 29;354(1389):1601-9. doi: 10.1098/rstb.1999.0504.


In unstimulated cells the transcription factor NF-kappa B is held in the cytoplasm in an inactive state by I kappa B inhibitor proteins. Ultimately activation of NF-kappa B is achieved by ubiquitination and proteasome-mediated degradation of I kappa B alpha and we have therefore investigated factors which control this proteolysis. Signal-induced degradation of I kappa B alpha exposes the nuclear localization signal of NF-kappa B, thus allowing it to translocate into the nucleus and activate transcription from responsive genes. An autoregulatory loop is established when NF-kappa B induces expression of the I kappa B alpha gene and newly synthesized I kappa B alpha accumulates in the nucleus where it negatively regulates NF-kappa B-dependent transcription. As part of this post-induction repression, the nuclear export signal on I kappa B alpha mediates transport of NF-kappa B-I kappa B alpha complexes from the nucleus to the cytoplasm. As nuclear export of I kappa B alpha is blocked by leptomycin B this drug was used to examine the effect of cellular location on susceptibility of I kappa B alpha to signal-induced degradation. In the presence of leptomycin B, I kappa B alpha is accumulated in the nucleus and in this compartment is resistant to signal-induced degradation. Thus signal-induced degradation of I kappa B alpha is mainly, if not exclusively a cytoplasmic process. An efficient nuclear export of I kappa B alpha is therefore essential for maintaining a low level of I kappa B alpha in the nucleus and allowing NF-kappa B to be transcriptionally active upon cell stimulation. We have detected a modified form of I kappa B alpha, conjugated to the small ubiquitin-like protein SUMO-1, which is resistant to signal-induced degradation. SUMO-1 modified I kappa B alpha remains associated with NF-kappa B and thus overexpression of SUMO-1 inhibits the signal-induced activation of NF-kappa B-dependent transcription. Reconstitution of the conjugation reaction with highly purified proteins demonstrated that in the presence of a novel E1 SUMO-1 activating enzyme, Ubch9 directly conjugated SUMO-1 to I kappa B alpha on residues K21 and K22, which are also used for ubiquitin modification. Thus, while ubiquitination targets proteins for rapid degradation, SUMO-1 modification acts antagonistically to generate proteins resistant to degradation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • DNA-Binding Proteins / metabolism*
  • Homeostasis
  • Humans
  • I-kappa B Proteins*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • SUMO-1 Protein
  • Signal Transduction*
  • Transcriptional Activation*
  • Ubiquitins / metabolism


  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • SUMO-1 Protein
  • Ubiquitins
  • NF-KappaB Inhibitor alpha