What is NF-κB?

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. NF-κB was first identified in 1986 as a transcription factor with specific binding affinity for the decameric DNA sequence 5-GGGACTTTCC-3 located within the enhancer of the immunoglobulin kappa light chain gene in mature B and plasmacells. It was subsequently shown that pathogen-derived products as well as cytokines and ultraviolet radiation induce NF-κB DNA-binding activity independent of new protein synthesis both in lymphocytes and nonlymphoid cells.

Two Distinct NF-κB Signaling Pathways:

Nuclear factor kappa B (NF-κB) is an ancient protein transcription factor and considered a regulator of innate immunity. The NF-κB signaling pathway links pathogenic signals and cellular danger signals thus organizing cellular resistance to invading pathogens. In fact, a plethora of studies have shown NF-κB is a network hub responsible for complex biological signaling.

Activation of NF-κB results generally as a consequence of signal transduction through one of two different routes. These are referred to as the canonical and the noncanonical NF-κB signaling pathways (Fig.1). Through the canonical NF-κB pathway, diverse stimuli engage immune receptors leading to rapid but transient activation of NF-κB (Fig.1, left).

In comparison to the canonical NF-κB signaling pathway, activation of NF-κB through the noncanonical pathway generally exhibits delayed kinetics and results in a more persistent NF-κB transcriptional response (Fig.1, right). Typically, the noncanonical NF-κB pathway is activated by developmental signals through specific receptors, including lymphotoxin β receptor (LTβR), B cell-activating factor receptor (BAFF-R), or CD40.

Figure 1 Canonical and noncanonical NF-κB pathways.

The NF-κB Family Transcription Factors:

In mammals, five different polypeptide subunits—RelA (p65), RelB, c-Rel, p50, and p52—associate with one another to generate functional NF-κB homo or heterodimers (Fig.2). Each of the five NF-κB subunits shares a high degree of amino acid conservation within an N-terminal region that spans roughly 300 residues, and which is referred to as the Rel homology region (RHR). X-ray crystallographic analyses have revealed that the RHR contains three independent structural elements: the N-terminal domain (NTD), the dimerization domain (DD), and the nuclear localization signal (NLS). Both NTD and DD are folded, globular domains, whereas the structure of the region including the NLS depends upon its interactions with other proteins. NF-κB RelA, RelB, and c-Rel subunits, but not p50 or p52, also contain unique amino acid sequences C-terminal to their respective RHR that are responsible for conveying transcriptional activation (TA).

Figure 2 Members of the NF-κB family

NF-κB Subunit Dimerization:

The DD of NF-κB proteins is capable of folding and assembling separately from the rest of the NF-κB RHR. This has enabled a detailed analysis of the biochemical processes that underlie NF-κB subunit dimerization selectivity. The DD is solely responsible for dimer formation, which occurs by juxtaposing two domains side-to-side with C2 point symmetry. A set of conserved amino acid residues from each subunit participate in mediating dimer formation. One of the most thermodynamically stable NF-κB dimer interfaces is the one that corresponds to the ubiquitous p50: RelA heterodimer (Fig.2, top).

Significance of the NF-κB:

The NF-κB (Nuclear factor kappa B) transcription factor plays crucial roles in the regulation of numerous biological processes including development of the immune system, inflammation, and innate and adaptive immune responses.

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