CSN controls NF-kappaB by deubiquitinylation of IkappaBalpha.
The COP9 signalosome (CSN) is a conserved protein complex that regulates assembly and activity of cullin-RING ubiquitin ligases (CRLs). Ubiquitin-dependent degradation of the NF-kappaB inhibitor IkappaBalpha preceeds nuclear translocation of NF-kappaB. For the first time, we show here an inducible interaction of the CSN with IkappaBalpha and that the CSN controls IkappaBalpha and NF-kappaB activity. Strikingly, disruption of the CSN by a small interfering RNA-mediated knockdown of single CSN subunits results in a reduced re-accumulation of IkappaBalpha and prolonged nuclear translocation of NF-kappaB in TNFalpha-stimulated cells. The control of IkappaBalpha by the CSN is regulated by deubiquitinylation of IkappaBalpha conferred by the CSN-associated deubiquitinylase USP15. Protein expression levels of cullin1 and the CRL substrate adapter beta-TrCP are reduced in nonstimulated cells with a disrupted function of the CSN, which might account for an impaired basal turnover of IkappaBalpha. We propose that the CSN controls both CRL activity and stability of the CRL substrate IkappaBalpha. In consequence, basal and signal-induced CRL-dependent turnover of IkappaBalpha is precisely adapted to specific cellular needs.
Schweitzer
Katrin
K
Medical Faculty, Institute of Experimental Internal Medicine, Otto-von-Guericke-University, Magdeburg, Germany.
Bozko
Przemyslaw M
PM
Dubiel
Wolfgang
W
Naumann
Michael
M
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000075686:COP9 Signalosome Complex; D024202:Electrophoretic Mobility Shift Assay; D010450:Endopeptidases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D047468:Immunoprecipitation; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D014452:Ubiquitins / Q000378:metabolism*
D020672:I-kappa B Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014452:Ubiquitins; D000072000:NF-KappaB Inhibitor alpha; D010450:Endopeptidases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases