The Regulatory Logic of the NF-kB Signaling System

NF-kB refers to multiple dimers of Rel homology domain (RHD) containing polypeptides, which are controlled bya stimulus-responsive signaling system that mediates the physiological responses to inflammatory intercellular cytokines, pathogen exposure, and developmental signals. TheNF-kBsignalingsystemoperatesontransientor short timescales, relevant to inflammation and immune responses, and on longer-term timescales relevant to cell differentiation and organ formation. Here, we summarize our current understanding of the kinetic mechanisms that allow for NF-kB regulation at these different timescales. We distinguish between the regulation of NF-kB dimer formation and the regulation of NF-kB activity. Given the number of regulators and reactions involved, the NF-kB signaling system is capable of integrating a multitude of signals to tune NF-kB activity, signal dose responsiveness, and dynamic control. We discuss the prevailing mechanisms that mediate signaling cross talk.