The regulatory logic of the NF-kappaB signaling system

Abstract

NF-kappaB refers to multiple dimers of Rel homology domain (RHD) containing polypeptides, which are controlled by a stimulus-responsive signaling system that mediates the physiological responses to inflammatory intercellular cytokines, pathogen exposure, and developmental signals. The NF-kappaB signaling system operates on transient or 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-kappaB regulation at these different timescales. We distinguish between the regulation of NF-kappaB dimer formation and the regulation of NF-kappaB activity. Given the number of regulators and reactions involved, the NF-kappaB signaling system is capable of integrating a multitude of signals to tune NF-kappaB activity, signal dose responsiveness, and dynamic control. We discuss the prevailing mechanisms that mediate signaling cross talk.

Figure 1.

Molecular components of the IKK–IκB–NF-κB signaling system. The IκB kinases form canonical NEMO-containing (green) complexes and noncanonical IKKα complexes (blue), which control the degradation of IκB proteins as well as precursor processing. IκBα, IκBβ, IκBε, p105 (IκBγ), and p100 (IκBδ) are able to bind and sequester NF-κB dimers (“IκB activity”). The p50 and p52 NF-κB proteins are initially synthesized as the precursor proteins p105 and p100, respectively. The five NF-κB family members can potentially form 15 possible dimers, which may bind to a large family of κB sites in DNA.

Figure 2.

Mechanisms determining NF-κB dimer generation. (A) Synthesis of RHD polypeptides and their dimerization affinities control the generation of NF-κB dimers, whose relative abundances in MEFs are indicated by their relative size. Green arrows indicate regulation by canonical IKK and the blue arrow regulation by noncanonical IKK. The amount of processing of the p105 and p100 proteins alters the amount of p50 and p52 available for dimer interaction, and abundances of certain subunits is influenced by the amount of others. (B) IκB-NF-κB interactions may play a role in dimer generation. A theoretical model of NF-κB dimer metabolism indicates that dimerizaton may reduce monomer degradation (if deg3<deg2 and/or deg1), and further, that IκB interactions with the dimer may not only block dimer dissociation into monomers, but also dimer degradation (if deg4<deg3).

Figure 3.

Mechanisms controlling stimulus-responsive NF-κB activities. Canonical signals activate NEMO-containing IKK complexes (green), which degrade the canonical IκB proteins (IκBα, β, and ε) and the IκBγ activity (composed of asymmetric p105 dimers) associated with NF-κB dimers. Released NF-κB dimers move to the nucleus to activate gene expression programs, including the expression of IκBα, IκBε, p105, p100, cRel, and RelB proteins. Noncanonical signals activate IKKα complexes, which degrade IκBδ complexes associated with NF-κB dimers. The resulting increase in synthesis of p100 and RelB, concomitant with IKKα activity, causes increased p100 processing to p52 and dimerization with RelB, to generate active RelB:p52 dimers to the nucleus. Stress signals can activate the eIF2α kinases, causing phosphorylation of eIF2α and resulting in inhibited translation. A block in IκB synthesis, in combination with constitutive IKK activity, results in the loss of IκB proteins and subsequent NF-κB dimer activation.