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.

SUBMITTER: Schweitzer K 

PROVIDER: S-EPMC4717852 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature