A pervasive role of ubiquitin conjugation in activation and termination of IκB kinase pathways

The nuclear factor (NF)-kappa B pathway is a paradigm for gene expression control by ubiquitin-mediated protein degradation. In stimulated cells, phosphorylation by the I kappa B kinase (IKK) complex primes NF-kappa B-inhibiting I kappa B molecules for lysine (Lys)-48-linked polyubiquitination and subsequent destruction by the 26S proteasome. However, recent studies indicate that the ubiquitin (Ub) system controls NF-kappa B pathways at many levels. Ub ligases are activated by different upstream signalling pathways, and they function as central regulators of IKK and c-Jun amino-terminal kinase activation. The assembly of Lys 63 polyUb chains provides docking surfaces for the recruitment of IKK-activating complexes, a reaction that is counteracted by deubiquitinating enzymes. Furthermore, Ub conjugation targets upstream signalling mediators as well as nuclear NF-kappa B for post-inductive degradation to limit the duration of signalling.