Innate sense of purpose for IKKβ.

The innate immune response is initiated upon recognition of pathogen-associated molecular patterns (PAMPs) by germ-line encoded pattern-recognition receptors (PRRs). PRRs including transmembrane receptors, typified by the Toll-like receptors (TLR) and cytoplasmic receptors, including the RIG-I– like receptors (RLRs), trigger signal transduction cascades culminating in the activation of transcription factors that regulate innate antimicrobial immune responses and induction of adaptive immunity. Members of the NF-κB and IFN regulatory factor (IRF) families of transcription factors are the key targets of PRR ligation and together regulate transcription of a broad array of antimicrobial effectors, including defensins, chemokines, and cytokines that orchestrate the immune response to pathogen invasion. Two articles in PNAS (1, 2) identify a new mechanism of cross-talk between the NFκB and IRF immune signaling pathways and position the kinase IKKβ as a master regulator of innate immunity. The mammalian NF-κB family consists of five Rel proteins: p65 (RelA), c-Rel, p52, p50, and RelB (3). In the steady state, NF-κB homoor heterodimers are sequestered in the cytoplasm through binding to inhibitor of κB (IκB) proteins. When a PRR is engaged by a cognate PAMP, a signaling cascade results in activation of the IκB kinase (IKK) complex (Fig. 1). The IKK complex consists of two kinase subunits, IKKα and IKKβ, and a regulatory subunit, NF-κB essential modulator (NEMO). The dominant pathway triggered by PRR activation is the canonical NF-κB pathway, where IKKβ-dependent phosphorylation of IκBα or IκBβ leads to their ubiquitination and degradation by the proteasome, resulting in nuclear translocation of the bound p65-, c-Rel–, and p50-containing heterodimers. The nuclear NF-κB dimers bind to κBDNA sites and activate a transcriptional program that includes numerous effectors of the innate immune response. The mammalian IRF family of transcription factors consists of nine members (IRF1– 9) that regulate the expression of a variety of genes, including genes encoding type I IFN (4). IRF3 and IRF7 have been the most widely studied and their mechanisms of activation downstream of PRR engagement and target genes are well characterized. Upon ligation of a TLR or RLR, signaling leads to activation of the IKK-family kinases TANK binding kinase 1 (TBK1) or IKKe (5). TBK1 is the dominant regulator of IRF3 and IRF7 activation in vivo, although there is partial redundancy with IKKe (6–9). TBK1/IKKe phosphorylate IRF3 or IRF7, resulting in a conformational change that promotes homodimerization, nuclear translocation, and expression of target genes.