Inducible NF-κB activation is-permitted by simultaneous degradation of nuclear IκBα

Abstract

Signal-induced phosphorylation and ubiquitination of IκBα targets this inhibitor of NF-κB for proteasome-mediated degradation, thus permitting the release of active NF-κB. Upon cell stimulation, NF-κB activation results in neo-transcription and neosynthesis of its own inhibitor, IκBα. As reported earlier, the neosynthesized inhibitor is then accumulated in the nucleus, where it rapidly binds to and terminates the function of nuclear NF-κB upon withdrawal of the stimulus. The present work was aimed at understanding how NF-κB activity is preserved while stimuli persist, despite intense, simultaneous IκBα neosynthesis, which would be expected to end NF-κB activity. We here show that incoming IκBα in the nucleus represents a target for resident nuclear proteasome complexes. Signal-induced, proteasome- dependent degradation of phosphorylated and ubiquitinated IκBα occurs in the nucleus, thus permitting the onset and persistence of NF-κB activity as long as stimulation is maintained. Our results suggest that intranuclear proteolysis of IκBα is necessarily required to avoid serf-termination of NF-κB activity during cell activation.