In mammals, there are five members of the transcription factor NF-κB family: RelA (p65), RelB and c-Rel, and the precursor proteins NF-κB1 (p105) and NF-κB2 (p100), which are processed into p50 and p52, respectively. NF-κB transcription factors bind as dimers to κB sites in promoters and enhancers of a variety of genes and induce or repress transcription. All NF-κB proteins share a Rel homology domain responsible for DNA binding and dimerization. Bacterial and viral infection, inflammatory cytokines and engagement of antigen receptors all elicit NF-κB activation, which highlights the crucial role of this transcription factor in the orchestration of immunity. The range of NF-κB-inducing stimuli further extends to physical, physiological and oxidative stresses, and its additional functions include regulation of cell differentiation, proliferation and survival. As a consequence, dysregulation of NF-κB activity is linked to inflammatory disorders, autoimmune and metabolic diseases, as well as cancer. 
Overall, two main NF-κB-activating pathways exist in cells. The canonical pathway is induced by most physiological NF-κB stimuli; for example, signals emanating from cytokine receptors, such as the tumor necrosis factor receptor (TNFR) and interleukin 1 (IL-1) receptor (IL-1R), antigen receptors and pattern-recognition receptors, including Toll-like receptor 4 (TLR4). The canonical pathway is defined as dependent on IKKβ and NEMO and leads mainly to phosphorylation of IκBα and nuclear translocation of mostly p65-­containing heterodimers. In contrast, the noncanonical pathway depends on IKKα-mediated phosphorylation of p100 associated with RelB and leads to partial processing of p100 and the generation of p52-RelB complexes. Noncanonical signaling is induced by specific members of the TNF cytokine family, such as CD40 ligand, BAFF and lymphotoxin-β2.


1.Oeckinghaus A,et al. Nat Immunol. 2011;12(8):695–708.