| c-Rel belongs to the Rel/NF-κB family of transcription factors characterized by a Rel homology domain that mediates DNA binding, dimerization, and nuclear localization. The protein contains an N-terminal Rel homology domain encompassing DNA-binding and dimerization regions, along with C-terminal transactivation domains unique to RelA, c-Rel, and RelB members. In resting hematopoietic cells where c-Rel expression predominates, IκBα and IκBβ sequester c-Rel dimers in the cytoplasm through binding to the nuclear localization signal within the Rel homology domain. Proinflammatory stimuli trigger the IKK complex to phosphorylate IκBα at N-terminal serines, leading to its K48-linked ubiquitination and proteasomal degradation, which unmasks the c-Rel nuclear localization signal and enables nuclear translocation as p50/c-Rel or RelA/c-Rel heterodimers. These dimers bind κB sites in promoters of target genes encoding cytokines, anti-apoptotic factors, and cell cycle regulators via the Rel homology domain's DNA-binding region. Distinct domains of IκBα mediate cytoplasmic retention through N-terminal and central ankyrin repeats that mask the nuclear localization signal, while central ankyrin and C-terminal acidic residues suffice for nuclear inhibition by competing for DNA-binding sites or corepressors. c-Rel forms stable p65/c-Rel heterodimers with IκBβ in unstimulated states, where hyperphosphorylated IκBβ acts as an inhibitor until stimulus-induced slow phosphorylation triggers its partial degradation, selectively releasing p65/c-Rel for TNFα promoter activation. Nuclear IκBα colocalizes with constitutively nuclear c-Rel variants to suppress transactivation. In T cell differentiation, c-Rel induces RORγt and IL-21 expression critical for Th17 and Tfh lineages, while supporting Foxp3 in regulatory T cells. Elevated c-Rel activity drives lymphoid malignancies and chronic inflammation through persistent target gene expression. |
Lane 1: Hela, Lane 2: C2C12, Lane 3: H-4-II-E, Lane 4: COS-7
