Destabilization of the VCP-Ufd1-Npl4 complex is associated with decreased levels of ERAD substrates.

Journal Article (Journal Article)

p97/VCP associated with Ufd1-Npl4 is considered a key player in ER-associated degradation (ERAD). RNA interference (RNAi) of one component of the Ufd1-Npl4 heterodimer destabilizes the VCP-Ufd1-Npl4 complex inducing proteasome-dependent degradation of the other component and releasing free VCP. In contrast to RNAi of VCP, RNAi of Ufd1 or Npl4 depleting approximately 90% of the VCP-Ufd1-Npl4 complexes does not induce unfolded protein response, indicating that the Ufd1-Npl4 dimer is not involved in the regulation of ER function by VCP. RNAi of Ufd1 or Npl4 is associated with a 2-fold increase in the levels of polyubiquitinated proteins, which form dispersed aggregates often associated with calnexin-positive structures. However, contrary to the effects of proteasome inhibition, RNAi of Ufd1 or Npl4 does not induce an accumulation of alpha-TCR and delta-CD3, two ERAD substrates overexpressed in HeLa cells. Instead, a 60-70% decrease in their levels is observed. The decrease in alpha-TCR levels is associated with a 50% decrease of its half-life. Upregulation of the putative channel forming protein, derlin-1, may contribute to the increased degradation of ERAD substrates. To explain our findings, we propose a model, where association of emerging ERAD substrates with VCP-Ufd1-Npl4 is not required for their degradation but has a regulatory role.

Full Text

Duke Authors

Cited Authors

  • Nowis, D; McConnell, E; Wójcik, C

Published Date

  • September 2006

Published In

Volume / Issue

  • 312 / 15

Start / End Page

  • 2921 - 2932

PubMed ID

  • 16822501

Electronic International Standard Serial Number (EISSN)

  • 1090-2422

International Standard Serial Number (ISSN)

  • 0014-4827

Digital Object Identifier (DOI)

  • 10.1016/j.yexcr.2006.05.013


  • eng