NF-κB signaling

Abstract

The NF-κB transcription factor is a critical regulator of the immune system, and is responsive to a large number of stimuli. Different stimuli engage signaling pathways to activate NF-κB, and effect distinct cellular responses. Mathematical modeling of the NF-κB network has been useful in studying the dynamic and cross-talk regulation of NF-κB. In this review, we discuss the regulation of NF-κB activity in response to different types of stimuli, including inflammatory signals, developmental cues, metabolic stress, and DNA damage. The distinct molecular mechanisms engaged in each pathway for activating and terminating NF-κB activity are discussed. In addition, we summarize the evidence for cross-talk mechanisms that allow for different stimuli to be integrated within the NF-κB signaling module to produce synergistic or qualitatively different signaling outcomes.

FIGURE 1

The components of the NF-κB signaling system a) The NF-κB family members. The gene name is indicated for each polypeptide. Each NF-κB family member has a Rel Homology Domain (RHD) for dimerization and DNA binding. RelA, cRel, and RelB have Transcriptional Activation Domains (TAD). b) The 5 NF-κB monomers can combine to form 15 potential dimers. Of these, 9 can bind DNA and activate gene transcription (light grey), 3 (the p50 or p52 only containing dimers) bind DNA but do not activate transcription (medium grey), and 3 do not bind DNA (dark grey). c) The IκB protein family members and signals that induce the degradation of each. The ARDs on p105 and p100 (which are proteolytically processed to p50 and p52 NF-κB monomers, respectively) can act to self-inhibit p50 and p52. p100 can form a multimeric complex in which it can inhibit other latent NF-κB dimers. BCR = B cell receptor; TCR = T cell receptor RHD = Rel Homology Domain; ARD = ankyrin repeat domain; TAD = transcriptional activation domain, SRD = signal response domain.

FIGURE 2

(a) Intuitive depiction of canonical NF-κB activation. Canonical (inflammatory) signals activate IKKβ-containing complexes (also contain NEMO and possibly IKKα), which target NF-κB-bound IκBα, β, and ε for degradation. IκBα, β, and ε that is not bound to NF-κB is constitutively degraded through an IKK- and ubiquitin-independent mechanism. Liberated NF-κB (primarily RelA:p50 dimers) translocates to the nucleus and activates gene expression, including the IκBα and IκBε genes. (b) Navigational map of canonical NF-κB activation. Canonical signals activate the IKK complex, which inhibits the IκBs, thus removing the inhibitory effect of IκB on NF-κB. NF-κB is then free to translocate to the nucleus and activate gene expression. The color coding corresponds to the intuitive depiction in (a).

FIGURE 3

(a) Intuitive depiction of NF-κB activation by metabolic stress (UV) and by DNA damage. UV irradiation activates the stress response kinases GCN2 or PERK, which phosphorylate the initiation factor elF2α. Phosphorylated elF2α prevents translation initiation, blocking IκB synthesis. Free IκB is rapidly depleted, preventing the replenishment of NF-κB-bound IκB that is slowly degraded through constitutive IKK activity, and NF-κB is slowly liberated and passes to the nucleus. Certain agents cause double stranded breaks in DNA. This triggers the phosphorylation of ATM, which associates with sumoylated NEMO in the nucleus, causing subsequent phosphorylation and ubiquitination of NEMO, and export to the cytoplasm where the complex of NEMO and phosphorylated ATM associate with the ELKS protein and stimulate activity of IKKβ containing complexes, causing degradation of IκBα and subsequent NF-κB translocation to the nucleus. (b) Navigational map of NF-κB activation by metabolic stress (UV) and DNA damage. UV irradiation induced activation of the stress kinases GCN2 and PERK results in the inhibition of the translation inhibition factor elF2α. The resulting inhibition of IκB synthesis allows for NF-κB translocation to the nucleus. DNA damage activates ATM, which associates with nuclear sumoylated NEMO, causing ubiquitination of NEMO and subsequent export to the cytoplasm. In the cytoplasm, the NEMO/ATM complex associates with the ELKs protein and activates IKK to induce NF-κB translocation to the nucleus. The color coding corresponds to the intuitive depiction in (a).

FIGURE 4

(a) Intuitive depiction of NF-κB activation by non-canonical signals. Non-canonical signals (developmental cues) activate IKKα containing complexes, which phosphorylate the C-terminal region of a p100 molecule within a multimeric complex (IκBδ), causing partial degradation of the p100 molecule (processing) and releasing associated RelA containing complexes. Hours later, the ratio of RelB associated with p100 is increased, and IKKα-dependent processing of de novo synthesized p100 leads to more RelB and p52 containing dimers. This requires RelA driven constitutive synthesis of RelB and p100. (b) Navigational map of NF-κB activation by non-canonical signals. Early activation of IKKα-containing complexes initiates the processing of a p100 molecule within the IκBδ complex. This removes the inhibitory action of IκBδ activity on RelA-containing NF-κB dimers, allowing for translocation to the nucleus. Hours later, the ratio of RelB associated with p100 is increased, and IKKα-dependent processing of de novo synthesized p100 leads to more RelB and p52 containing dimers, which translocate to the nucleus to effect gene expression. The color coding corresponds to the intuitive depiction in (a).

FIGURE 5

NF-κB responses to metabolic stresses. NF-κB activation in response to metabolic stresses that cause translational inhibition was computationally simulated as a function of the level of basal/constitutive IKK activity. (a) Simulations of nuclear NF-κB (nM in color scale) after 8 hours of the indicated degree of translational repression (% on the x-axis) at indicated levels of constitutive IKK activity (y-axis). (b) Simulations of nuclear NF-κB fold-induction (nuclear NF-κB at 8 hours over nuclear basal NF-κB) after 8 hours of the indicated degree of translational inhibition (% on the x-axis) at indicated levels of constitutive IKK activity (y-axis). The IKK activity multiplier is the degree to which the wild-type level of constitutive IKK activity (1% of the IKK is active in the “wild-type model”) was multiplied by during the equilibration phase, prior to the induction of translational repression and held constant throughout each simulation.