Cellular dynamics of NF-kappaB regulation

The NFκB/Rel protein family is important in normal physiological processes and pathogenesis. Regulation of NFκB/Rel has been viewed as static control of nuclear import that completely depends on inducible IκBα degradation. My results showed that IκBα is a shuttling protein and nuclear export is critical for maintaining a cytoplasmic pool of NFκB/Rel. IκBα export is mediated by a nuclear export sequence (NES) located in the N-terminal signal receptor domain of IκBα. RelA (p65), but not c-Rel, also has an NES at the C-terminus that contributes to its cytoplasmic localization. A third mechanism of cytoplasmic localization is the differential attenuation of nuclear localization sequences in Rel protein by IκBs. These observations suggest an ordered removal of different NFκB/Rel homo- or heterodimers from the nucleus. Furthermore, different IκBs were shown to perform similar functions, such as the cytoplasmic retention of NFκB/Rel, with distinct mechanisms. In contrast to IκBα, IκBβ and IκBϵ used a true sequestration mechanism to retain NFκB/Rel owing to their lack of export function and closer association with NFκB/Rel NLS. The elucidation of import and export potential in both IκBα and Rel proteins prompts me to revisit the NFKκB regulation at a different level.; The differential kinetics, coupled with the differential association of IκB with NFκB/Rel may provide a plausible mechanisms for the cell-specific and subunit-specific expression of nuclear NFκB/Rel in B lymphocytes. A hallmark of B lymphocyte is the presence of nuclear c-Rel/p50. The fast turnover rate of IκBα in B cells probably creates a nuclear pool of c-Rel-containing NFκB/Rel and p65-containing NFκB/Rel. However, p65-containing NFκB/Rel is efficiently exported because of its additional p65 NES. The nuclear propensity of p50/c-Rel is further enhanced by the inefficient attenuation of p50 NLS. This explains the predominance of nuclear p50/c-Rel in B lymphocytes. The cell specificity may result from the preferential c-Rel association with some other cytoplasmic tethering proteins such as IκBβ in other cells. Despite the lack of c-Rel/IκBα complexes in resting T cells, c-Rel transiently associates with hypophosphorylated IκBα after TNFα activation, indicating that increased affinity of NFκB/Rel to newly synthesized IκBα may facilitate NFκB/Rel export during down-regulation.