Activation by IKKα of a Second, Evolutionary Conserved, NF-κB Signaling Pathway

TLDR

In mammals, the canonical NF‑κB pathway activated by infections relies on IKK‑mediated degradation of IkappaB inhibitors, with IKKβ essential for IkappaB phosphorylation while IKKα is not. IKKα preferentially phosphorylates NF‑κB2 (p100), a step that requires upstream kinases such as NIK, leading to regulated processing of the precursor. IKKα is required for B‑cell maturation, secondary lymphoid organ formation, upregulation of specific NF‑κB target genes, and is a pivotal component of a second NF‑κB activation pathway based on NF‑κB2 processing rather than IkappaB degradation.

Abstract

In mammals, the canonical nuclear factor kappaB (NF-kappaB) signaling pathway activated in response to infections is based on degradation of IkappaB inhibitors. This pathway depends on the IkappaB kinase (IKK), which contains two catalytic subunits, IKKalpha and IKKbeta. IKKbeta is essential for inducible IkappaB phosphorylation and degradation, whereas IKKalpha is not. Here we show that IKKalpha is required for B cell maturation, formation of secondary lymphoid organs, increased expression of certain NF-kappaB target genes, and processing of the NF-kappaB2 (p100) precursor. IKKapla preferentially phosphorylates NF-kappaB2, and this activity requires its phosphorylation by upstream kinases, one of which may be NF-kappaB-inducing kinase (NIK). IKKapla is therefore a pivotal component of a second NF-kappaB activation pathway based on regulated NF-kappaB2 processing rather than IkappaB degradation.