NFkB1

NFkB1, also written NFKB1, is a gene that encodes a member of the NF-κB family of transcription factors. In humans, the NFKB1 gene is located on chromosome 4q24. The gene product is the 105 kDa precursor protein p105, which is proteolytically processed to the 50 kDa subunit p50. The p105 precursor contains an N-terminal Rel homology domain and C-terminal ankyrin repeats; upon processing, the resulting p50 subunit lacks a transactivation domain.

The NF-κB1 protein forms dimers with other NF-κB family members, most commonly RelA/p65, to regulate transcription. p50-containing dimers bind κB motifs in DNA and control genes involved in immune and inflammatory responses, cell survival, and development. In resting cells, NF-κB dimers are sequestered in the cytoplasm by inhibitors known as IκBs. Stimulation by cytokines, microbial products, or stress activates the IκB kinase (IKK) complex, leading to phosphorylation and ubiquitin-mediated degradation of IκB. This releases NF-κB to translocate to the nucleus, where it binds DNA and modulates transcription.

Clinical significance: Germline mutations in NFKB1, particularly haploinsufficient or dominant-negative variants, are associated with common variable immunodeficiency (CVID) and immune dysregulation, including increased susceptibility to infections and autoimmunity. Somatic alterations of NFKB1 have been observed in various cancers, especially B-cell–related malignancies, underscoring its role in oncogenic signaling.

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