Nuclear factor kappa B (NFkB) is a rapid acting primary transcription factor that regulates the transcription of specific pro-inflammatory genes. Although it is found in nearly all animal cells types, it was first discovered interacting with a DNA sequence important for producing light chains in B cells. Therefore, it plays a key role in regulating immune response to infections. Irregularities of NFkB signaling have been associated with cancer, inflammation, and improper immune development.
NFkB is a heterodimer protein composed of different combinations of members of the Rel family of transcription factors involved in inflammatory responses. There are two structural classes of NFkB: class I (p50/p105) and class II (RelA(p65)/RelB). p105 undergoes proteolytic cleavage to generate mature p50 subunit. Class I and II dimerize to form the complete NFkB subunit. Both classes contain a Rel Homology Region (N terminus, DNA binding domain and Ligand Binding domain). The DNA binding domain not only allows NFkB to bind to promoter regions in the DNA but it also allows it to bind to I-kappa-beta-alpha (IkBα) protein, a member of a family of cellular proteins that function to inhibitor NFkB transcription factor by masking nuclear localization signals, keeping NFkB sequestered in the cytoplasm. In the C terminus, Class I contains glycine rich repeats that can inhibit transcription, while Class II contains a transcription activating domain.
NFkB signaling pathway is stimulated by various ligands, such as, LPS, TNF, inflammatory cytokines, lymphokines, and viral/bacterial gene products. Usually, NFkB is held in an inactive state in the cytoplasm by its inhibitor IkBα. The inhibitor masks its nuclear localization signal. Upon ligand binding the receptor will activate a series of steps leading to phosphorylation of IkBa at serine residues (32 and 36) which marks it for degradation via ubiquitylation and proteasomal processing. The destruction of IkBa then liberates NFkB which translocates to the nucleus and activates specific genes leading to physiological responses such as inflammation, cell survival, or cell proliferation. NFkB needs to be regulated otherwise it can promote inflammatory diseases, like arthritis, asthma, and atherosclerosis and production of cancers.