Figure 5. Proposed mechanism for the activation of IKKβ by IL-1 in IKKα-deficient MEFs.

IL-1 stimulates the formation of hybrid ubiquitin chains in which LUBAC-generated Met¹-linked ubiquitin oligomers are attached covalently to TRAF6-generated Lys⁶³-linked ubiquitin oligomers. The binding of Lys⁶³-linked ubiquitin to TAB2 or TAB3 activates the TAK1 complex by inducing autophosphorylation of the catalytic subunit at Thr¹⁸⁷ [31]. The M1-linked ubiquitin chains interact with NEMO permitting TAK1 to phosphorylate IKKβ at Ser¹⁷⁷. Phosphorylation of Ser¹⁷⁷ allows autophosphorylation of Ser¹⁸¹. The activated IKKβ can then phosphorylate IκBα. Sites of phosphorylation are denoted by ‘P’.