Akt Regulates Basal and Induced Processing of NF-κB2 (p100) to p52

NF-κB is a family of transcription factors important for innate and adaptive immunity. NF-κB is restricted to the cytoplasm by inhibitory proteins that are degraded when specifically phosphorylated, permitting NF-κB to enter the nucleus and activate target genes. Phosphorylation of the inhibitory proteins is mediated by an IκB kinase (IKK) complex, which can be composed of two subunits with enzymatic activity, IKKα and IKKβ. The preferred substrate for IKKβ is IκBα, degradation of which liberates p65 (RelA) to enter the nucleus where it induces genes important to innate immunity. IKKα activates a non-canonical NF-κB pathway in which p100 (NF-κB2) is processed to p52. Once produced, p52 can enter the nucleus and induce genes important to adaptive immunity. This study shows that Akt binds to and increases the activity of IKKα and thereby increases p52 production in cells. Constitutively active Akt augments non-canonical NF-κB activity, whereas kinase dead Akt or inhibition of phosphatidylinositol 3-kinase have the opposite effect. Basal and ligand-induced p52 production is reduced in mouse embryo fibroblasts deficient in Akt1 and Akt2 compared with parental cells. These observations show that Akt plays a role in activation of basal and induced non-canonical NF-κB activity.