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.
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
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
Cell
Date: Oct. 13, 2000
PubMed ID: 11057907
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