The mechanistic relationship of phosphorylation of the C terminus of IKKbeta with phosphorylation of its T-loop kinase domain within the IKK complex remained unclear. We investigated the regulatory role of the serine cluster residing immediately adjacent to the HLH domain and of the serines in the NEMO/IKKgamma-binding domain (NBD/gammaBD) in the C-terminal portion of IKKbeta in MEFs deficient in IKKbeta and IKKalpha and in yeast reconstitution system. We show that phosphorylation events at the C terminus of IKKbeta can be divided into autophosphorylation of the serine cluster adjacent to the HLH domain and phosphorylation of the NBD/gammaBD. Autophosphorylation of the serine cluster occurs immediately after IKK activation and requires IKKgamma. In MEFs, this autophosphorylation does not have the down-regulatory function on the IKK complex that was previously described (1). On the other hand, phosphorylation of the NBD/gammaBD regulates IKKgamma-dependent phosphorylation of the T-loop activation domain in IKKbeta and, hence, IKK complex activation. Our study suggests that, within the IKK complex, modulation of the NBD/gammaBD by IKKgamma is upstream to the T-loop phosphorylation.
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