Are the IKKs and IKK-related kinases TBK1 and IKK-ɛ similarly activated?

The IκB kinases (IKKs) IKK-α and IKK-β, and the IKK-related kinases TBK1 and IKK-ɛ, have essential roles in innate immunity through signal-induced activation of NF-κB, IRF3 and IRF7, respectively. Although the signaling events within these pathways have been extensively studied, the mechanisms of IKK and IKK-related complex assembly and activation remain poorly defined. Recent data provide insight into the requirement for scaffold proteins in complex assembly; NF-κB essential modulator coordinates some IKK complexes, whereas TANK, NF-κB-activating kinase-associated protein 1 (NAP1) or similar to NAP1 TBK1 adaptor (SINTBAD) assemble TBK1 and IKK-ɛ complexes. The different scaffold proteins undergo similar post-translational modifications, including phosphorylation and non-degradative polyubiquitylation. Moreover, increasing evidence indicates that distinct scaffold proteins assemble IKK, and potentially TBK1 and IKK-ɛ subcomplexes, in a stimulus-specific manner, which might be a mechanism to achieve specificity. * Authors contributed equally to this work.