Overview of NF-κB pathway

In mammals, the NF-κB family is composed of five related transcription factors: p50, p52, RelA (p65), c-Rel, and RelB^1,2. These transcription factors share homology through a 300 amino acid N-terminal DNA binding/dimerization domain, called the Rel homology domain (RHD). The RHD is a platform where family members can form homodimers and heterodimers, enabling them to bind promoters and enhancer regions of genes to modulate their expression.

RelA, c-Rel, and RelB contain C-terminal transcriptional activation domains (TADs), which enable them to activate target gene expression. In contrast, p50 and p52 do not contain C-terminal TADs; therefore, p50 and p52 homodimers repress transcription unless they are bound to a protein containing a TAD, such as RelA, c-Rel or RelB or Bcl-3 (a related transcriptional co-activator). Unlike the other NF-κB family members, p50 and p52 are derived from larger precursors, p105 and p100, respectively.

NF-κB proteins are inhibited by IκB proteins present in the cytoplasm. There are currently seven identified IκB family members: IκBα, IκBβ, Bcl-3, IκBε, IκBγ, and the precursor proteins p100 and p105, which are characterized by the presence of ankyrin repeats. 

​In the canonical signaling pathway, binding of a ligand to a cell surface receptor such as a member of the Toll-like receptor superfamily leads to the recruitment of adaptors (such as TRAF) to the cytoplasmic domain of the receptor (Figure 1). These adaptors in turn recruit the IKK complex, which leads to phosphorylation and degradation of the IκB inhibitor. The canonical pathway activates NF-κB dimers comprising RelA, c-Rel, RelB, and p50.

The non-canonical pathway is responsible for the activation of p100/RelB complexes and occurs during the development of lymphoid organs responsible for the generation of B and T lymphocytes (Figure 2). Only a small number of stimuli are known to activate NF-κB via this pathway and these factors include lymphotoxin B and B cell-activating factor (BAFF).

This pathway involves an IKK complex that contains two IKKα subunits, but not NEMO. In the non-canonical pathway, ligand-induced activation triggers NF-κB inducing kinase (NIK) to phosphorylate and activate the IKKα complex. In turn, the IKKα complex phosphorylates p100 leading to the processing and liberation of the p52/RelB active heterodimer.