Origin of the Functional Distinctiveness of NF-κB/p52

Abstract

The transcription regulators of the NF-κB family have emerged as a critical factor affecting the function of various adult tissues. The NF-κB family transcription factors are homo- and heterodimers made up of five monomers (p50, p52, RelA, cRel and RelB). The family is distinguished by sequence homology in their DNA binding and dimerization domains, which enables them to bind similar DNA response elements and participate in similar biological programs through transcriptional activation and repression of hundreds of genes. Even though the family members are closely related in terms of sequence and function, they all display distinct activities. In this review, we discuss the sequence characteristics, protein and DNA interactions, and pathogenic involvement of one member of family, NF-κB/p52, relative to that of other members. We pinpoint the small sequence variations within the conserved region that are mostly responsible for its distinct functional properties.

Unusual Association of NF-κB Components in Tumor-Associated Macrophages (TAMs) Promotes HSPG2-Mediated Immune-Escaping Mechanism in Breast Cancer

“…In the canonical NF-κB activation pathway, the heterodimeric RelA/p65-NFKB1 complex appeared to be the most abundant, while in the non-canonical one, the NFKB2/p100 phosphorylation and processing induced the formation of the heterodimeric RelB-p52 complex [ 15 ]. Surprisingly, both RelB and NFKB1 showed no significant changes in macrophages, suggesting that a specific activation of NFKB2 and RelA could promote the formation of an unusual heterodimeric p65/p52 complex, correlated to HSPG2 transcriptional regulation.…”

“…These features allow binding to similar DNA response elements in the genome, and participation in similar biological programs, through transcriptional activation and repression of hundreds of genes. Despite the close relationship between the NF-κB family members, they all show distinct activities [ 15 ].…”

Atypical IκB Bcl3 enhances the generation of the NF-κB p52 homodimer

“…Function of this homodimer is yet to be fully explored. Frontiers in Cell and Developmental Biology frontiersin.org Synthesis of p100, the precursor of p52, is mediated primarily by RelA dimers which is the product of the NF-κB canonical signaling; however, the maturation of p100 into p52 requires the non-canonical signaling (Ghosh and Wang, 2021). Since the NF-κB dimer generated by most known non-canonical signals is the p52:RelB heterodimer, it has remained an open question how the p52:p52 homodimer is formed.…”

Impaired thymic AIRE expression underlies autoantibodies against type I IFNs in humans with inborn errors of the alternative NF-kB pathway

“…The active form, p52 can bind DNA, but, like NF-κB1 (p105/p50), and unlike RelA, RelB, and cRel, it lacks a transcriptional activation domain (TAD). Its transcriptional activation, thus, requires heterodimerization with another TADcontaining REL protein 65 . The p52 protein predominantly dimerizes with RelB in vivo, but an excess of p52 can lead to p52/p52 homodimerization occurring in vitro, potentially repressing the κB-site transcriptional activity of other dimers though a dosage effect 63,64 (Fig.…”

“…In resting cells, the processing inhibitory domain (PID) of p100 protects against the spontaneous processing and nuclear translocation of the p100 precursor. Unprocessed cytoplasmic p100 can form high molecular weight complexes by homo-multimerization (generating kappaBsomes) via its C-terminal IκB-like domain, thereby inhibiting the DNA-binding activity of almost all NF-κB subunits (this is referred to as IκBδ function) [65][66][67] . In the mouse thymus, RANK and the alternative NF-κB pathway, thus, play a crucial role in mTECs by governing self-tolerance 58,60 .…”