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

doi:10.15252/embr.201439123

Journal articles

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

Esther Marza ^{1, 2} Saïd Taouji ² Kim Barroso ^{2, 3} Anne-Aurélie Raymond ⁴ Léo Guignard ^{5, 6, 1} Marc Bonneu ⁷ Néstor Pallares-Lupon ² Jean-William Dupuy ⁷ Martin E. Fernandez-Zapico ⁸ Jean Rosenbaum ² Francesca Palladino ⁹ Denis Dupuy ¹ Eric Chevet ^{2, 3}

1 ARNA - Régulations Naturelles et Artificielles

2 Physiopathologie du cancer du foie

3 OSS - Oncogenesis Stress Signaling

4 IPBS - Institut de pharmacologie et de biologie structurale

5 CRBM - Centre de recherche en Biologie Cellulaire

6 VIRTUAL PLANTS - Modeling plant morphogenesis at different scales, from genes to phenotype

CRISAM - Inria Sophia Antipolis - Méditerranée , INRA - Institut National de la Recherche Agronomique, UMR AGAP - Amélioration génétique et adaptation des plantes méditerranéennes et tropicales

7 CGFB - Centre Génomique Fonctionnelle Bordeaux [Bordeaux]

8 Schulze Center for Novel Therapeutics, Division of Oncology Research [Rochester]

9 LBMC - Laboratoire de Biologie Moléculaire de la Cellule

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 : UPR AAA+ ATPase proteostasis

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Journal articles

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Life Sciences [q-bio] / Cancer

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Submitted on : Monday, June 15, 2015 - 2:09:59 PM
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Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription

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

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