title: Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription.
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.
authors: Team "Endoplasmic Reticulum stress and cancer", INSERM, UMR1053, Bordeaux, France University of Bordeaux, Bordeaux, France ARNA laboratory, INSERM U869, Bordeaux, France.
authors: Esther
authors: E
authors: Marza
authors: Team "Endoplasmic Reticulum stress and cancer", INSERM, UMR1053, Bordeaux, France University of Bordeaux, Bordeaux, France.
authors: Saïd
authors: S
authors: Taouji
authors: Team "Endoplasmic Reticulum stress and cancer", INSERM, UMR1053, Bordeaux, France University of Bordeaux, Bordeaux, France.
authors: Kim
authors: K
authors: Barroso
authors: University of Bordeaux, Bordeaux, France "REPTeam", INSERM, UMR1053, Bordeaux, France.
authors: Anne-Aurélie
authors: AA
authors: Raymond
authors: University of Bordeaux, Bordeaux, France ARNA laboratory, INSERM U869, Bordeaux, France.
authors: Léo
authors: L
authors: Guignard
authors: University of Bordeaux, Bordeaux, France Plateforme Proteome, Bordeaux, France.
authors: Marc
authors: M
authors: Bonneu
authors: Team "Endoplasmic Reticulum stress and cancer", INSERM, UMR1053, Bordeaux, France University of Bordeaux, Bordeaux, France.
authors: Néstor
authors: N
authors: Pallares-Lupon
authors: University of Bordeaux, Bordeaux, France Plateforme Proteome, Bordeaux, France.
authors: Jean-William
authors: JW
authors: Dupuy
authors: Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
authors: Martin E
authors: ME
authors: Fernandez-Zapico
authors: University of Bordeaux, Bordeaux, France "REPTeam", INSERM, UMR1053, Bordeaux, France.
authors: Jean
authors: J
authors: Rosenbaum
authors: Laboratory of Molecular and Cellular Biology, Ecole Normale Supérieure, CNRS UMR5239 Université de Lyon, Lyon Cedex 07, France.
authors: Francesca
authors: F
authors: Palladino
authors: University of Bordeaux, Bordeaux, France ARNA laboratory, INSERM U869, Bordeaux, France.
authors: Denis
authors: D
authors: Dupuy
authors: 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.
authors: Eric
authors: E
authors: Chevet
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic / Q000502:physiology*; D056811:Unfolded Protein Response / Q000502:physiology*; D000074405:Valosin Containing Protein
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D012097:Repressor Proteins; D000251:Adenosine Triphosphatases; C000603329:RUVB-2 protein, C elegans; D000074405:Valosin Containing Protein
keywords: AAA+ ATPase; UPR; proteostasis
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