A fourth IκB protein within the NF-κB signaling module

Inflammatory NF-kappa B/RelA activation is mediated by the three canonical inhibitors, I kappa B alpha, -beta, and -epsilon. We report here the characterization of a fourth inhibitor, nf kappa b2/p100, that forms two distinct inhibitory complexes with RelA, one of which mediates developmental NF-kappa B activation. Our genetic evidence confirms that p100 is required and sufficient as a fourth I kappa B protein for noncanonical NF-kappa B signaling downstream of NIK and IKK1. We develop a mathematical model of the four-I kappa B-containing NF-kappa B signaling module to account for NF-kappa B/BelA: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 I kappa B 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.