Nuclear factor-κB (NF-κB) consists of a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, and survival. Inducible NF-κB activation depends on phosphorylation-induced proteosomal degradation of the inhibitor of NF-κB proteins (IκBs), which retain inactive NF-κB dimers in the cytosol in unstimulated cells. The majority of the diverse signaling pathways that lead to NF-κB activation converge on the IκB kinase (IKK) complex, which is responsible for IκB phosphorylation and is essential for signal transduction to NF-κB.

The eukaryotic transcription factor, Nuclear Factor-κB (NF-κB), was initially identified by Sen and Baltimore nearly 20 years ago as a regulator of the intronic enhancer of the immunoglobulin kappa light chain gene in mature B and plasma cells. By recent estimates, the human genome contains an estimated 14,000 binding sites for NF-κB so it should come as no surprise that since its discovery, NF-κB has rightfully earned the renown of being a protean of transcription factors. The vast repertoire of NF-κB binding sites in the genome is emblematic of its wide-ranging regulatory functions, encompassing immune responses, proliferation, differentiation, apoptosis, and stress responses. Thus, given the scope of its regulation, the discovery of NF-κB seems nothing short of a biological tour de force.

In mammals, the transcription factor nuclear factor kappa B (NF-κB) family consists of five different DNA-binding subunits belonging to the Rel family of proteins: p65 (RelA), RelB, c-Rel, p50/pl05 (NF-κB 1) and p52/pl00 (NF-κB 2). Notably, the DNA-binding subunits of p50 and p52 are derived from proteolytic processing of their precursors pl05 and p100, respectively. All Rel proteins share a conserved motif, the Rel homology domain (RHD) which is located at the N-termin us and consists of approximately 300 amino acids. The RHD is responsible for dimerization, DNA-binding to KB sites, nuclear localization and interaction with inhibitors of NF-κB (IKBS). Meanwhile, the transactivation domain (TAD) that is necessary for NF-κB-dependent transcriptional activity is present only in the C-terminus of p65, RelB and c-Rel. By contrast, p50 and p52 lack TADs, rendering them transcriptionally inactive unless complexed with a TAD-containing member. Alternatively, p50 and p52 can form homodimers and bind KB sites to repress transcription. In most cell types, NF-κB subunits exist as hetero- or homodimers bound to inhibitory IKB proteins - a mechanism designed to retain the complex in the cytoplasm.

Pathways to NF-κB Activation

NF-κB is sensitive to a plethora of stimuli, including pro-inflammatory cytokines, responses, but also modulate cell survival and proliferation. Hence, NF-κB participates in a number of biological processes, including .

Canonical Pathway of NF-κB Activation

The canonical pathway is triggered by various immune receptors, such Toll-like receptors, interleukin-1 receptor (IL-1R), tumor necrosis factor receptor (TNFR), and antigen receptors. Upon ligand engagement, a cascade of signal transduction events culminate in the activation of the classical IicB-kinase (IKK) complex, which includes two catalytic subunits, IKKa and IKKp, and a scaffold protein, NF-κB essential modulator (NEMO; IKKγ). After activation, IKK phosphorylates IKBOI, predominantly via the action of IKKp, triggering its lysine-48-linked polyubiquitination and proteasomal degradation. IKBCX masks only the p65 NLS, whereas the p50 NLS remains exposed and is responsible, together with the IKBCX nuclear-export sequence, for shuttling IκBα-NF-κB complexes between the nucleus and the cytoplasm. IKBO, degradation reveals the p65 NLS, thereby promoting rapid NF-κB translocation into the nucleus. By virtue of its nuclear translocation, NF-κB is poised to bind DNA and activate target gene transcription.

Alternative Pathway of NF-κB Activation

The second, alternative pathway is activated by a subset of NF-κB inducers, including lymphotoxin-P, BAFF and CD40 ligand. This pathway occurs predominantly in B cells, where the p52/RelB heterodimer is the major NF-κB dimer. The alternative NF-κB pathway is NEMO-independent and relies solely on the sequential activation of NIK and IKKa, which in turn induces the processing of pl00 to p52. The liberated p52 forms a functional heterodimer with RelB, which translocates into the nucleus where it stimulates transcription of genes that are important for secondary lymphoid organ development, B-cell homeostasis and adaptive immunity.


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