In contrast to the canonical NF-κB pathway, the noncanonical NF-κB pathway selectively responds to a specific group of stimuli, including ligands of a subset of TNFR superfamily members such as LTβR, BAFFR, CD40 and RANK. 9 Upon activation, IKK phosphorylates IκBα at two N-terminal serines and, thereby, triggers ubiquitin-dependent IκBα degradation in the proteasome, resulting in rapid and transient nuclear translocation of canonical NF-κB 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, IKKα and IKKβ, and a regulatory subunit named NF-κB essential modulator (NEMO) or IKKγ. 6 The primary mechanism for canonical NF-κB activation is the inducible degradation of IκBα triggered through its site-specific phosphorylation by a multi-subunit IκB kinase (IKK) complex. 3, 5 The canonical NF-κB 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-κB 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-κB1 and NF-κB2, p105 and p100, serve as IκB-like proteins, because their C-terminal potion resembles the structure of IκB and has NF-κB inhibitory functions. 3 To date, the best studied and most important IκB family member is IκBα. 2 The NF-κB proteins are normally sequestered in the cytoplasm by a family of inhibitory proteins, including IκB family members and related proteins characterized by the presence of ankyrin repeats. 1 This family is composed of five structurally related members, including NF-κB1 (also named p50), NF-κB2 (also named p52), RelA (also named p65), RelB and c-Rel, which mediates transcription of target genes by binding to a specific DNA element, κB enhancer, as various hetero- or homo-dimers. Nuclear factor-κB (NF-κB) represents a family of inducible transcription factors, which regulates a large array of genes involved in different processes of the immune and inflammatory responses.
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