1. Academic Validation
  2. p97/VCP promotes Cullin-RING-ubiquitin-ligase/proteasome-dependent degradation of IκBα and the preceding liberation of RelA from ubiquitinated IκBα

p97/VCP promotes Cullin-RING-ubiquitin-ligase/proteasome-dependent degradation of IκBα and the preceding liberation of RelA from ubiquitinated IκBα

  • J Cell Mol Med. 2016 Jan;20(1):58-70. doi: 10.1111/jcmm.12702.
Katrin Schweitzer 1 Alexander Pralow 1 Michael Naumann 1
Affiliations

Affiliation

  • 1 Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany.
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.

Keywords

Cop9 signalosome; NF-κB; TNF.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15713
    99.87%, VCP/p97 抑制剂
    p97