13, 14 The processing of p100 involves degradation of its C-terminal IОєB-like structure, resulting in generation of mature NF-ОєB2 p52 and nuclear translocation of the noncanonical NF-ОєB complex p52/RelB. 3, 11 A central signaling molecule for this pathway is NF-ОєB-inducing kinase (NIK), which activates and functionally cooperates with IKKО± to mediate p100 phosphorylation, which in turn induces p100 ubiquitination and processing.

11, 12 In addition, the noncanonical NF-ОєB activation does not involve IОєBО± degradation but rather relies on processing of the NF-ОєB2 precursor protein, p100. In contrast to the canonical NF-ОєB pathway, the noncanonical NF-ОєB pathway selectively responds to a specific group of stimuli, including ligands of a subset of TNFR superfamily members such as LTОІR, BAFFR, CD40 and RANK. 9 Upon activation, IKK phosphorylates IОєBО± at two N-terminal serines and, thereby, triggers ubiquitin-dependent IОєBО± degradation in the proteasome, resulting in rapid and transient nuclear translocation of canonical NF-ОєB members predominantly the p50/RelA and p50/c-Rel dimers. 8 IKK can be activated by different stimuli, including cytokines, growth factors, mitogens, microbial components and stress agents. 1, 7 IKK is composed of two catalytic subunits, IKKО± and IKKОІ, and a regulatory subunit named NF-ОєB essential modulator (NEMO) or IKKОі. 6 The primary mechanism for canonical NF-ОєB activation is the inducible degradation of IОєBО± triggered through its site-specific phosphorylation by a multi-subunit IОєB kinase (IKK) complex. 3, 5 The canonical NF-ОєB pathway responds to diverse stimuli, including ligands of various cytokine receptors, pattern-recognition receptors (PRRs), TNF receptor (TNFR) superfamily members, as well as T-cell receptor (TCR) and B-cell receptor. The activation of NF-ОєB involves two major signaling pathways, the canonical and noncanonical (or alternative) pathways, both being important for regulating immune and inflammatory responses despite their differences in signaling mechanism.

In addition, the precursor proteins of NF-ОєB1 and NF-ОєB2, p105 and p100, serve as IОєB-like proteins, because their C-terminal potion resembles the structure of IОєB and has NF-ОєB inhibitory functions. 3 To date, the best studied and most important IОєB family member is IОєBО±. 2 The NF-ОєB proteins are normally sequestered in the cytoplasm by a family of inhibitory proteins, including IОєB family members and related proteins characterized by the presence of ankyrin repeats. 1 This family is composed of five structurally related members, including NF-ОєB1 (also named p50), NF-ОєB2 (also named p52), RelA (also named p65), RelB and c-Rel, which mediates transcription of target genes by binding to a specific DNA element, ОєB enhancer, as various hetero- or homo-dimers.

Nuclear factor-ОєB (NF-ОєB) represents a family of inducible transcription factors, which regulates a large array of genes involved in different processes of the immune and inflammatory responses.

Mio map activation key