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

Esther Marza, Saïd Taouji, Kim Barroso, Anne Aurélie Raymond, Léo Guignard, Marc Bonneu, Néstor Pallares-Lupon, Jean William Dupuy, Martin E. Fernandez-Zapico, Jean Rosenbaum, Francesca Palladino, Denis Dupuy, Eric Chevet

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPRER) 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 UPRER 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 UPRER 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 UPRER 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. Synopsis During ER stress, p97/CDC-48 mediates reptin degradation thereby enabling both ATF6 activation and XBP1 mRNA splicing. This work uncovers another layer in the regulation of canonical ER stress signaling. p97/CDC-48 induces reptin degradation upon ER stress. Reptin is a repressor of both ATF6 activation and XBP1 mRNA splicing. p97/cdc-48-mediated retpin degradation promotes ER adaptive response to stress. During ER stress, p97/CDC-48 mediates reptin degradation thereby enabling both ATF6 activation and XBP1 mRNA splicing. This work uncovers another layer in the regulation of canonical ER stress signaling.

Original languageEnglish (US)
Pages (from-to)332-340
Number of pages9
JournalEMBO Reports
Volume16
Issue number3
DOIs
StatePublished - Mar 1 2015

Keywords

  • AAA ATPase
  • UPR
  • proteostasis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription'. Together they form a unique fingerprint.

Cite this