NF-κB activation is tightly regulated mainly through its localization. In resting cells, NF-κB proteins are kept in the cytoplasm in association with inhibitory IkB proteins including IκBα, IκBβ, and IκBε [15] among which IκBα is the most abundant. NF-κB signaling occurs through the canonical (classical) pathway initiated by NF-κB1 (p50/p105) and a noncanonical (alternative) pathway initiated by NF-κB2 (p52/p100) (Fig 1). Before the active NF-κB is translocated into the nucleus, NF-κB1 and NF-κB2 are cleaved to the active p50 and p52 subunits, respectively. While the classical pathway depends on IKK complex consisting of IKKα, IKKβ, IKKγ and the inhibitory subunit IκBs, the alternative pathway depends on IKKα homodimers and NF-κB inducing kinase (NIK) [17–19]. During classical activation, the IKK complex specifically phosphorylates IκBs on two conserved N-terminal serine residues which target them for E2- and E3-ligase-mediated polyubiquitination and subsequent 26S proteasomal mediated degradation. This process releases and activates NF-κB which now translocates to the nucleus. The activation of alternative pathway, which is commonly associated with RelB results in regulated processing of the p100 precursor protein to p52 and subsequent translocation
