NFKBIA Gene: Function, Mutations, and Associated Diseases | IκBα

The NFKBIA gene encodes the protein IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), a member of the IκB family. IκBα is a key cytoplasmic inhibitor of the NF-κB transcription factor complex. In unstimulated cells, IκBα binds to NF-κB dimers (typically p50/p65) and sequesters them in the cytoplasm, preventing their nuclear translocation and DNA binding. Upon stimulation by various signals (e.g., cytokines, pathogens, stress), IκBα is phosphorylated by the IKK complex, ubiquitinated, and degraded by the proteasome, allowing NF-κB to enter the nucleus and activate transcription of target genes involved in immune response, inflammation, cell survival, and proliferation. Thus, NFKBIA is a critical negative regulator of NF-κB signaling.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• NF-kappaB signaling pathway

• Toll-like receptor signaling pathway

• TNF signaling pathway

• B cell receptor signaling pathway

• T cell receptor signaling pathway

• Cytokine-cytokine receptor interaction

• Apoptosis

• Inflammatory mediator regulation of TRP channels

IκBα (UniProt P25963) is a 317-amino acid protein with ankyrin repeat domains that mediate binding to NF-κB dimers. It contains N-terminal regulatory serines (Ser32 and Ser36) that are phosphorylated by IKK, and a C-terminal PEST domain involved in constitutive degradation. IκBα shuttles between nucleus and cytoplasm, but predominantly retains NF-κB in the cytoplasm. Its degradation is a key step in NF-κB activation. Mutations affecting its phosphorylation or degradation lead to dysregulated NF-κB signaling, with pathological consequences.