P97/VCP promotes Cullin-RING-ubiquitin-ligase/proteasome-dependent degradation of I?B? and the preceding liberation of RelA from ubiquitinated I?B?.

ABSTRACT: Cullin-RING-ubiquitin-ligase (CRL)-dependent ubiquitination of the nuclear factor kappa B (NF-?B) inhibitor I?B? and its subsequent degradation by the proteasome usually precede NF-?B/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-?B activation independent of Ub-proteasome-pathway (UPP)-dependent turnover of I?B? in some studies, a strict requirement of the p97/VCP ATPase for both, I?B? degradation and NF-?B activation, was reported in others. In this study, we thus aimed to reconcile the mechanism for tumour necrosis factor (TNF)-induced NF-?B activation. We found that inducible phosphorylation of RelA is accomplished in an IKK-complex-dependent manner within the NF-?B/RelA-I?B?-complex contemporaneous with the phosphorylation of I?B?, and that RelA phosphorylation is not sufficient to dissociate NF-?B/RelA from I?B?. Subsequent to CRL-dependent I?B? ubiquitination functional p97/VCP is essentially required for efficient liberation of (phosphorylated) RelA from I?B?, preceding p97/VCP-promoted timely and efficient degradation of I?B? as well as simultaneous NF-?B/RelA nuclear translocation. Collectively, our data add new facets to the knowledge about maintenance of I?B? and RelA expression, likely depending on p97/VCP-supported scheduled basal NF-?B activity, and the mechanism of TNF-induced NF-?B activation.

SUBMITTER: Schweitzer K 

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

REPOSITORIES: biostudies-other