Inducible NF-kappa B activation is permitted by simultaneous degradation of nuclear I kappa B alpha

Signal-induced phosphorylation and ubiquitination of I kappa B alpha target s this inhibitor of NF-kappa B for proteasome-mediated degradation, thus pe rmitting the release of active NF-kappa B. Upon cell stimulation, NF-kappa B activation results in neo-transcription and neosynthesis of its own inhib itor, I kappa B alpha, As reported earlier, the neosynthesized inhibitor is then accumulated in the nucleus, where it rapidly binds to and terminates the function of nuclear NF-kappa B upon withdrawal of the stimulus. The pre sent work was aimed at understanding how NF-kappa B activity is preserved w hile stimuli persist, despite intense, simultaneous I kappa B alpha neosynt hesis, which would be expected to end NF-kappa B activity. We here show tha t incoming I kappa B alpha in the nucleus represents a target for resident nuclear proteasome complexes. Signal-induced, proteasome-dependent degradat ion of phosphorylated and ubiquitinated I kappa B alpha! occurs in the nucl eus, thus permitting the onset and persistence of NF-kappa B activity as lo ng as stimulation is maintained. Our results suggest that intranuclear prot eolysis of I kappa B alpha is necessarily required to avoid self-terminatio n of NF-kappa B activity during cell activation.