Abstract

Cytokine-induced activation of the IkappaB kinases (IKK) IKK-alpha and IKK-beta is a key step involved in the activation of the NF-kappaB pathway. Gene-disruption studies of the murine IKK genes have shown that IKK-beta, but not IKK-alpha, is critical for cytokine-induced IkappaB degradation. Nevertheless, mouse embryo fibroblasts deficient in IKK-alpha are defective in the induction of NF-kappaB-dependent transcription. These observations raised the question of whether IKK-alpha might regulate a previously undescribed step to activate the NF-kappaB pathway that is independent of its previously described cytoplasmic role in the phosphorylation of IkappaBalpha. Here we show that IKK-alpha functions in the nucleus to activate the expression of NF-kappaB-responsive genes after stimulation with cytokines. IKK-alpha interacts with CREB-binding protein and in conjunction with Rel A is recruited to NF-kappaB-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone H3. These results define a new nuclear role of IKK-alpha in modifying histone function that is critical for the activation of NF-kappaB-directed gene expression.