p52p100

p52 and p100 are related members of the NF-κB transcription factor family, often discussed as the p52/p100 pair. In humans, p100 is produced from the NFKB2 gene as a large precursor protein, and a proteolytic processing event generates the smaller p52 subunit, which then participates in transcription regulation. The full-length p100 contains an N-terminal Rel homology region for DNA binding and dimerization, followed by a C-terminal domain rich in ankyrin repeats that inhibits its activity by retaining it in the cytoplasm. Processing removes the C-terminal inhibitory region to yield p52, enabling nuclear localization and DNA binding in partnership with other NF-κB subunits, most notably RelB.

Activation of p100 processing occurs mainly through the noncanonical NF-κB signaling pathway. Stimuli such as BAFF, CD40 ligand, and RANKL activate IKKα, which phosphorylates p100. This triggers partial proteasomal processing that converts p100 into p52. The resulting p52 typically forms active dimers with RelB, driving transcription of target genes involved in lymphoid organ development, B cell maturation, and immune responses. As full-length p100, by contrast, can act as an inhibitor and sequester NF-κB subunits in the cytoplasm, limiting unintended signaling.

Functionally, p52-containing dimers regulate a subset of genes distinct from the canonical p50–RelA pathway, with particularly important roles in immune system development and function. Regulation of p100 processing and p52 activity is tightly controlled, and dysregulation can contribute to immune deficiencies and inflammation. Mutations or alterations in NFKB2, the gene encoding p100/p52, have been linked to immunodeficiency disorders such as CVID and various autoimmune phenotypes, highlighting the clinical relevance of the p52/p100 axis.