Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain

• Published in: Cell Vol. 103; no. 2; pp. 351 - 361
• Main Authors: Deng, Li, Wang, Chen, Spencer, Erika, Yang, Liyong, Braun, Amy, You, Jianxin, Slaughter, Clive, Pickart, Cecile, Chen, Zhijian J
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 13.10.2000
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)00126-4

TRAF6 is a signal transducer in the NF-κB pathway that activates IκB 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.