An unexpected twist to the activation of IKK{beta}: TAK1 primes IKK{beta} for activation by autophosphorylation

The IκB kinase β (IKKβ) is required to activate the transcription factor NF-κB, but how IKKβ itself is activated in vivo is still unclear. It was found to require phosphorylation by one or more “upstream” protein kinases in some reports but by auto-phosphorylation in others. Here, we resolve this controversy by demonstrating that the activation of IKKβ induced by IL-1 or TNF in embryonic fibroblasts, or by ligands that activate Toll-Like receptors in macrophages, requires two distinct phosphorylation events; first, the TAK1-catalysed phosphorylation of Ser177 and second the IKKβ-catalyzed auto-phosphorylation of Ser181. The phosphorylation of Ser177 by TAK1 is a priming event required for the subsequent autophosphorylation of Ser181, which enables IKKβ to phosphorylate exogenous substrates. We also provide genetic evidence which indicates that the IL-1-stimulated, LUBAC-catalysed formation of linear ubiquitin chains and their interaction with the NEMO component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKKβ at Ser177 and IKKα at Ser176. These findings may be of general significance for the activation of other protein kinases.
Source: BJ Signal - Category: Biochemistry Authors: Tags: BJ Signal Source Type: research