IκBβ enhances the generation of the low-affinity NFκB/RelA homodimer

The NFκB family of dimeric transcription factors regulate inflammatory and immune responses. While the dynamic control of NFκB dimer activity via the IκB–NFκB 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-NFκB generation module. Our study reveals that IκBβ has essential functions within the Rel-NFκB generation module, specifically for the RelA:RelA homodimer, which controls a subset of NFκB target genes. Our findings revise the current dogma of the three classical, functionally related IκB proteins by distinguishing between a positive ‘licensing’ factor (IκBβ) that contributes to determining the available NFκB dimer repertoire in a cell’s steady state, and negative feedback regulators (IκBα and -ɛ) that determine the duration and dynamics of the cellular response to an inflammatory stimulus. The NFκB signalling pathway is regulated through the formation of transcription factor dimers but mechanisms controlling their formation are poorly understood. Here, Tsui et al. report that IκBb is a positive regulator of Rel-NFκB dimer formation, using in vitro and in vivoexperiments and mathematical modelling.