Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway

In mammals, the canonical nuclear factor kappaB (NF-kappaB) signaling pathway activated in response to infections is based on degradation Of I kappaB inhibitors. This pathway depends on the I kappaB kinase (IKK), which contains two catalytic subunits, IKK alpha and IKK beta. IKK beta is essential for inducible I kappaB phosphorylation and degradation, whereas IKK alpha is not. Here we show that IKK alpha is required for B cell maturation, formation of secondary lymphoid organs, increased expression of certain NF-kappaB target genes, and processing of the NF-kappa B2 (p100) precursor. IKK alpha preferentially phosphorylates NF-kappa B2, and this activity requires its phosphorylation by upstream kinases, one of which may be NF-kappaB-inducing kinase (NIK). IKK alpha is therefore a pivotal component of a second NF-kappaB activation pathway based on regulated NF-kappa B2 processing rather than I kappaB degradation.