The transcription factor nuclear factor κB (NF-κB) controls cytokine-regulated processes and is regulated by the IκB kinase (IKK) complex comprising IKKα, IKKβ and IKKγ. Whereas IKKβ controls the degradation of inhibitors of NF-κB (IκBs) resulting in rapid nuclear accumulation of NF-κB, the role of the IKKα subunit has been more elusive. But now, reporting in Nature, the groups of Richard Gaynor and Albert Baldwin propose a new, nucleosomal function for IKKα.

Recent observations indicated that IKKα might have a role in cytokine-induced, NF-κB-dependent gene regulation, independent of that of IKKβ. Both groups showed that this role is likely to be nuclear, as cytokine induction resulted in the nuclear accumulation of IKKα but not IKKβ. To investigate the mechanism underlying IKKα's nuclear role, the groups carried out chromatin immunoprecipitation assays (ChIPs) and showed that, in response to tumour-necrosis factor (TNF)-α stimulation, IKKα was recruited to NF-κB-responsive gene promoters.

As interactions between coactivator CREB-binding protein (CBP) and NF-κB subunit p65 have been shown to be important for NF-κB activation, Gaynor and colleagues tried to establish whether IKKα functions through complex formation with these coactivators. Indeed, IKKα interacts with CBP, but not with p65. Both groups showed that in p65−/− cells, IKKα is not recruited to NF-κB-regulated promoters, indicating that p65 is required for IKKα–promoter association.

So how does IKKα modulate transcriptional activation? Given that histone H3 modifications have been correlated with active gene expression, the Gaynor and Baldwin groups carried out ChIP assays using phosphorylated histone H3 antibodies and found that the kinetics of IKKα recruitment and histone H3 serine (Ser) 10 phosphorylation correlated, and that TNF-α-induced Ser10 phosphorylation was abolished in IKKα−/− cells. Cytokine-induced phosphorylation of histone H3 was suggested to be due to the direct kinase activity of IKKα, as IKKα (but not IKKβ) was shown to phosphorylate H3 on Ser10 using in vitro kinase assays.

It has been proposed that histone H3 phosphorylation can cause the recruitment of histone acetyltransferase (HAT) activity. Indeed, both types of histone H3 modifications were reduced in IKKα−/− cells, indicating that IKKα-mediated phosphorylation of Ser10 is probably important for the subsequent acetylation of lysine (Lys) 14 in histone H3. Using ChIP assays and modified histone H3 antibodies, Gaynor and colleagues showed that cytokine stimulation of wild-type cells led to increased IKKα–promoter association and Ser10 phosphorylation and Lys14 acetylation of histone H3. CBP has HAT activity, and in IKKβ−/− cells, association of both CBP and acetylated histone H3 was reduced, indicating that CBP might provide the HAT activity that is responsible for Lys14 acetylation. The interaction of IKKα and CBP provides an efficient way to phosphorylate, and subsequently acetylate, histone H3, resulting in cytokine-induced activation of NF-κB-directed gene expression.

The authors concluded that their findings have identified IKKα as an essential player in NF-κB-regulated gene expression, thereby adding a new role to the several existing regulatory functions for IκB kinases in this process.