Inducible NF-kappaB activation is permitted by simultaneous degradation of nuclear IkappaBalpha.
Signal-induced phosphorylation and ubiquitination of IkappaBalpha targets this inhibitor of NF-kappaB for proteasome-mediated degradation, thus permitting the release of active NF-kappaB. Upon cell stimulation, NF-kappaB activation results in neotranscription and neosynthesis of its own inhibitor, IkappaBalpha. As reported earlier, the neosynthesized inhibitor is then accumulated in the nucleus, where it rapidly binds to and terminates the function of nuclear NF-kappaB upon withdrawal of the stimulus. The present work was aimed at understanding how NF-kappaB activity is preserved while stimuli persist, despite intense, simultaneous IkappaBalpha neosynthesis, which would be expected to end NF-kappaB activity. We here show that incoming IkappaBalpha in the nucleus represents a target for resident nuclear proteasome complexes. Signal-induced, proteasome-dependent degradation of phosphorylated and ubiquitinated IkappaBalpha occurs in the nucleus, thus permitting the onset and persistence of NF-kappaB activity as long as stimulation is maintained. Our results suggest that intranuclear proteolysis of IkappaBalpha is necessarily required to avoid self-termination of NF-kappaB activity during cell activation.
Renard
P
P
Unité d'Immunologie Virale, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France.
Percherancier
Y
Y
Kroll
M
M
Thomas
D
D
Virelizier
J L
JL
Arenzana-Seisdedos
F
F
Bachelerie
F
F
D002467:Cell Nucleus / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D009097:Multienzyme Complexes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D014452:Ubiquitins / Q000378:metabolism
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011994:Recombinant Proteins; D014452:Ubiquitins; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex