title: p97/VCP promotes Cullin-RING-ubiquitin-ligase/proteasome-dependent degradation of IκBα and the preceding liberation of RelA from ubiquitinated IκBα.
abstract: Cullin-RING-ubiquitin-ligase (CRL)-dependent ubiquitination of the nuclear factor kappa B (NF-κB) inhibitor IκBα and its subsequent degradation by the proteasome usually precede NF-κB/RelA nuclear activity. Through removal of the CRL-activating modification of their cullin subunit with the ubiquitin (Ub)-like modifier NEDD8, the COP9 signalosome (CSN) opposes CRL Ub-ligase activity. While RelA phosphorylation was observed to mediate NF-κB activation independent of Ub-proteasome-pathway (UPP)-dependent turnover of IκBα in some studies, a strict requirement of the p97/VCP ATPase for both, IκBα degradation and NF-κB activation, was reported in others. In this study, we thus aimed to reconcile the mechanism for tumour necrosis factor (TNF)-induced NF-κB activation. We found that inducible phosphorylation of RelA is accomplished in an IKK-complex-dependent manner within the NF-κB/RelA-IκBα-complex contemporaneous with the phosphorylation of IκBα, and that RelA phosphorylation is not sufficient to dissociate NF-κB/RelA from IκBα. Subsequent to CRL-dependent IκBα ubiquitination functional p97/VCP is essentially required for efficient liberation of (phosphorylated) RelA from IκBα, preceding p97/VCP-promoted timely and efficient degradation of IκBα as well as simultaneous NF-κB/RelA nuclear translocation. Collectively, our data add new facets to the knowledge about maintenance of IκBα and RelA expression, likely depending on p97/VCP-supported scheduled basal NF-κB activity, and the mechanism of TNF-induced NF-κB activation.
authors.affiliation: Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schweitzer
authors.affiliation: Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pralow
authors.affiliation: Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Naumann
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology*; D000075686:COP9 Signalosome Complex; D018797:Cell Cycle Proteins / Q000502:physiology*; D044842:Cullin Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D000075687:NEDD8 Protein; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D046912:Multiprotein Complexes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C498143:RELA protein, human; C439524:TNF protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D014452:Ubiquitins; D000072000:NF-KappaB Inhibitor alpha; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: Cop9 signalosome; NF-κB; TNF