IkBb enhances the generation of the low-affinity NFkB/RelA homodimer

The NFkB family of dimeric transcription factors regulate inflammatory and immune responses. While the dynamic control of NFkB dimer activity via the IkB–NFkB signalling module is well understood, there is little information on how specific dimer repertoires are generated from Rel family polypeptides. Here we report the iterative construction—guided by in vitro and in vivo experimentation—of a mathematical model of the Rel-NFkB generation module. Our study reveals that IkBb has essential functions within the Rel-NFkB generation module, specifically for the RelA:RelA homodimer, which controls a subset of NFkB target genes. Our findings revise the current dogma of the three classical, functionally related IkB proteins by distinguishing between a positive ‘licensing’ factor (IkBb) that contributes to determining the available NFkB dimer repertoire in a cell’s steady state, and negative feedback regulators (IkBa and -e) that determine the duration and dynamics of the cellular response to an inflammatory stimulus. DOI: 10.1038/ncomms8068