Nfkb2

NFKB2 is a gene that encodes the NF-kappa-B subunit p100, which is synthesized as an inactive cytoplasmic precursor. The p100 protein contains an N-terminal Rel homology domain used for DNA binding and dimerization, followed by C-terminal ankyrin repeats that confer inhibitory activity. In resting cells, p100 participates in cytoplasmic NF-κB complexes, helping to regulate signaling by sequestering certain NF-κB subunits and restricting their activity.

Activation of the noncanonical NF-κB signaling pathway drives the processing of p100 to the active p52 form. This processing is mediated by the kinase NIK (MAP3K14) and IKKα, which phosphorylate p100, targeting it for ubiquitin-proteasome–dependent processing. The resulting p52 then forms active transcription factor dimers, most notably with RelB, which translocate to the nucleus to regulate gene expression. The noncanonical pathway is typically stimulated by signals such as BAFF, CD40 ligand, and lymphotoxin-β receptor engagement, and it plays a key role in B cell maturation, lymphoid organ development, and adaptive immune responses.

Biological and clinical significance is tied to the proper function of NFKB2 in immune regulation. Animal models with Nfkb2 disruption show defects in secondary lymphoid organ development and impaired germinal center formation. In humans, germline mutations in NFKB2 have been linked to immunodeficiency disorders characterized by hypogammaglobulinemia and impaired B cell maturation, sometimes with autoimmunity or endocrine abnormalities. Somatic alterations and dysregulation of NFKB2 have been observed in certain B-cell malignancies, reflecting its role in lymphoid cell survival and proliferation. Overall, NFKB2 is a key component of the noncanonical NF-κB pathway with important roles in immune development and homeostasis.