Functions of NF-κB1 and NF-κB2 in immune cell biology

Abstract

Two members of the NF-κB (nuclear factor κB)/Rel transcription factor family, NF-κB1 and NF-κB2, are produced as precursor proteins, NF-κB1 p105 and NF-κB2 p100 respectively. These are proteolytically processed by the proteasome to produce the mature transcription factors NF-κB1 p50 and NF-κB2 p52. p105 and p100 are known to function additionally as IκBs (inhibitors of NF-κB), which retain associated NF-κB subunits in the cytoplasm of unstimulated cells. The present review focuses on the latest advances in research on the function of NF-κB1 and NF-κB2 in immune cells. NF-κB2 p100 processing has recently been shown to be stimulated by a subset of NF-κB inducers, including lymphotoxin-β, B-cell activating factor and CD40 ligand, via a novel signalling pathway. This promotes the nuclear translocation of p52-containing NF-κB dimers, which regulate peripheral lymphoid organogenesis and B-lymphocyte differentiation. Increased p100 processing also contributes to the malignant phenotype of certain T- and B-cell lymphomas. NF-κB1 has a distinct function from NF-κB2, and is important in controlling lymphocyte and macrophage function in immune and inflammatory responses. In contrast with p100, p105 is constitutively processed to p50. However, after stimulation with agonists, such as tumour necrosis factor-α and lipopolysaccharide, p105 is completely degraded by the proteasome. This releases associated p50, which translocates into the nucleus to modulate target gene expression. p105 degradation also liberates the p105-associated MAP kinase (mitogen-activated protein kinase) kinase kinase TPL-2 (tumour progression locus-2), which can then activate the ERK (extracellular-signal-regulated kinase)/MAP kinase cascade. Thus, in addition to its role in NF-κB activation, p105 functions as a regulator of MAP kinase signalling.