NFKB2
Description
The NFKB2 (nuclear factor kappa B subunit 2) is a protein-coding gene located on chromosome 10.
Nuclear factor NF-kappa-B p100 subunit is a protein that in humans is encoded by the NFKB2 gene.
NF-κB has been detected in numerous cell types that express cytokines, chemokines, growth factors, cell adhesion molecules, and some acute phase proteins in health and in various disease states. NF-κB is activated by a wide variety of stimuli such as cytokines, oxidant-free radicals, inhaled particles, ultraviolet irradiation, and bacterial or viral products. Inappropriate activation of NF-kappa-B has been linked to inflammatory events associated with autoimmune arthritis, asthma, septic shock, lung fibrosis, glomerulonephritis, atherosclerosis, and AIDS. In contrast, complete and persistent inhibition of NF-kappa-B has been linked directly to apoptosis, inappropriate immune cell development, and delayed cell growth. For reviews, see Chen et al. (1999) and Baldwin (1996).[supplied by OMIM]
Mutation of the NFKB2 gene has been linked to Common variable immunodeficiency (CVID) as the cause of the disease. Other genes might also be responsible. The frequency of NFKB2 mutation in CVID population is yet to be established. The protein NFKB2 can become mutated and lead to hereditary endocrine and immuneodeficiences. The mutation occurs at the C-terminus of NFKB2 and it causes common variable immunodeficienciency which in turn causes endocrine deficiency and immunodeficiencies.
NF-kappa-B is a crucial transcription factor found in virtually all cell types. It plays a key role in various biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis, and apoptosis. NF-kappa-B exists as a homo- or heterodimeric complex, composed of Rel-like domain-containing proteins including RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL, and NFKB2/p52. These dimers bind to specific DNA sequences known as kappa-B sites, influencing the expression of target genes. Each dimer combination exhibits distinct binding preferences, with some acting as transcriptional activators and others as repressors. NF-kappa-B is meticulously regulated through post-translational modifications, subcellular compartmentalization, and interactions with other cofactors or corepressors. Inactive NF-kappa-B complexes are retained in the cytoplasm, associated with members of the NF-kappa-B inhibitor (I-kappa-B) family. Upon activation, I-kappa-B undergoes phosphorylation by I-kappa-B kinases (IKKs) triggered by various stimuli. This phosphorylation event leads to I-kappa-B degradation, liberating the active NF-kappa-B complex, which then translocates to the nucleus. An alternative activation pathway, known as the non-canonical pathway, involves MAP3K14-activated CHUK/IKKA homodimer phosphorylating NFKB2/p100 associated with RelB. This phosphorylation induces proteolytic processing of NFKB2/p100 to NFKB2/p52, ultimately forming NF-kappa-B RelB-p52 complexes. The RelB-p52 heterodimer functions as a transcriptional activator, whereas the p52-p52 homodimer acts as a repressor. NFKB2 exhibits dual roles, contributing to cytoplasmic retention of associated NF-kappa-B proteins in its p100 form and generating p52 through cotranslational processing. This proteasome-mediated process ensures the production of both p52 and p100, allowing them to function independently. p52 binds to a specific DNA sequence, the kappa-B consensus sequence (5'-GGRNNYYCC-3'), located within the enhancer regions of genes implicated in immune responses and acute phase reactions. Although p52 and p100 are present, p100 is the dominant form, with the processing of p100 occurring relatively inefficiently. p49, an isoform of NFKB2, forms part of the NF-kappa-B protein complex, synergistically stimulating the HIV enhancer in conjunction with p65. p49, in collaboration with RELB, regulates the circadian clock by suppressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer.
NFKB2 is also known as CVID10, H2TF1, LYT-10, LYT10, NF-kB2, p100, p49/p100, p52.
Associated Diseases
- Immunodeficiency, common variable, 10
- Common variable immunodeficiency
- Deficiency in anterior pituitary function-variable immunodeficiency syndrome
