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Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain.

TRAF6 is a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. We have purified a heterodimeric protein complex that links TRAF6 to IKK activation. Peptide mass fingerprinting analysis reveals that this complex is composed of the ubiquitin conjugating enzyme Ubc13 and the Ubc-like protein Uev1A. We find that TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin. Blockade of this polyubiquitin chain synthesis, but not inhibition of the proteasome, prevents the activation of IKK by TRAF6. These results unveil a new regulatory function for ubiquitin, in which IKK is activated through the assembly of K63-linked polyubiquitin chains.

Pubmed ID: 11057907


  • Deng L
  • Wang C
  • Spencer E
  • Yang L
  • Braun A
  • You J
  • Slaughter C
  • Pickart C
  • Chen ZJ



Publication Data

October 13, 2000

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM 59203
  • Agency: NIGMS NIH HHS, Id: GM 60372

Mesh Terms

  • Amino Acid Sequence
  • Biopolymers
  • Cell-Free System
  • Cloning, Molecular
  • Dimerization
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Ligases
  • Molecular Sequence Data
  • Peptide Mapping
  • Polyubiquitin
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • TNF Receptor-Associated Factor 6
  • Transcription Factors
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases
  • Ubiquitins