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Abstract
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.