2. Academic Validation
  3. Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription

Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription

  • EMBO Rep. 2015 Mar;16(3):332-40. doi: 10.15252/embr.201439123.
Esther Marza 1,  Saïd Taouji 2,  Kim Barroso 2,  Anne-Aurélie Raymond 3,  Léo Guignard 4,  Marc Bonneu 5,  Néstor Pallares-Lupon 2,  Jean-William Dupuy 5,  Martin E Fernandez-Zapico 6,  Jean Rosenbaum 3,  Francesca Palladino 7,  Denis Dupuy 4,  Eric Chevet 8
Affiliations

Affiliations

  • 1 Team "Endoplasmic Reticulum stress and cancer", INSERM, UMR1053, Bordeaux, France University of Bordeaux, Bordeaux, France ARNA laboratory, INSERM U869, Bordeaux, France.
  • 2 Team "Endoplasmic Reticulum stress and cancer", INSERM, UMR1053, Bordeaux, France University of Bordeaux, Bordeaux, France.
  • 3 University of Bordeaux, Bordeaux, France "REPTeam", INSERM, UMR1053, Bordeaux, France.
  • 4 University of Bordeaux, Bordeaux, France ARNA laboratory, INSERM U869, Bordeaux, France.
  • 5 University of Bordeaux, Bordeaux, France Plateforme Proteome, Bordeaux, France.
  • 6 Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
  • 7 Laboratory of Molecular and Cellular Biology, Ecole Normale Supérieure, CNRS UMR5239 Université de Lyon, Lyon Cedex 07, France.
  • 8 Team "Endoplasmic Reticulum stress and cancer", INSERM, UMR1053, Bordeaux, France University of Bordeaux, Bordeaux, France Centre Régional de Lutte Contre le Cancer Eugène Marquis, Rennes, France eric.chevet@inserm.fr.
PMID: 25652260 DOI: 10.15252/embr.201439123
Abstract

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPR(ER)) to restore ER homeostasis. The AAA(+) ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPR(ER) genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA(+) ATPase, as a novel repressor of a subset of UPR(ER) genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPR(ER) genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes.

Keywords

AAA+ ATPase; UPR; proteostasis.

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