A Fourth IκB Protein within the NF-κB Signaling Module

Inflammatory NF-κB/RelA activation is mediated by the three canonical inhibitors, IκBα, -β, and -ɛ. We report here the characterization of a fourth inhibitor, nfκb2/p100, that forms two distinct inhibitory complexes with RelA, one of which mediates developmental NF-κB activation. Our genetic evidence confirms that p100 is required and sufficient as a fourth IκB protein for noncanonical NF-κB signaling downstream of NIK and IKK1. We develop a mathematical model of the four-IκB-containing NF-κB signaling module to account for NF-κB/RelA:p50 activation in response to inflammatory and developmental stimuli and find signaling crosstalk between them that determines gene-expression programs. Further combined computational and experimental studies reveal that mutant cells with altered balances between canonical and noncanonical IκB proteins may exhibit inappropriate inflammatory gene expression in response to developmental signals. Our results have important implications for physiological and pathological scenarios in which inflammatory and developmental signals converge.