Priming IKKβ kinase for action

IKKβ (IκB kinase β) is a core component of signalling pathways that control the activation of NF-κB (nuclear factor κB) transcription factors, which regulate many physiological processes, including cell survival, immunity and DNA-damage responses. Like many kinases, activation of IKKβ requires phosphorylation of the activation loop of its kinase domain. Different upstream protein kinases, and IKKβ itself, have been reported to directly phosphorylate and activate IKKβ in vitro, but the exact molecular mechanism of IKKβ activation in cells has remained unclear. In a recent article in the Biochemical Journal, Zhang and co-workers showed that IKKβ is activated by two sequential phosphorylations of its activation loop in response to TNF (tumour necrosis factor), IL-1 (interleukin-1) and TLR (Toll-like receptor) ligands. Using a combination of biochemical and genetic approaches, they demonstrate that IKKβ is first phosphorylated by the upstream kinase TAK1 [TGFβ (transforming growth factor β)-activated kinase-1] at Ser177, which then serves as a priming signal for subsequent IKKβ autophosphorylation at Ser181. This study resolves two apparently conflicting earlier models of IKKβ activation into a single unified model, and suggests that the IKKβ activation loop may integrate distinct ‘upsteam’ signals to activate NF-κB.