RRC ID 45797
Author Marza E, Taouji S, Barroso K, Raymond AA, Guignard L, Bonneu M, Pallares-Lupon N, Dupuy JW, Fernandez-Zapico ME, Rosenbaum J, Palladino F, Dupuy D, Chevet E.
Title Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription.
Journal EMBO Rep
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.
Volume 16(3)
Pages 332-40
Published 2015-3-1
DOI 10.15252/embr.201439123
PII embr.201439123
PMID 25652260
PMC PMC4364872
MeSH Adenosine Triphosphatases / genetics Adenosine Triphosphatases / metabolism* Animals Caenorhabditis elegans / physiology* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Endoplasmic Reticulum Stress / genetics Endoplasmic Reticulum Stress / physiology* Proteomics / methods RNA Interference Repressor Proteins / metabolism Signal Transduction / genetics* Transcription, Genetic / physiology* Unfolded Protein Response / physiology* Valosin Containing Protein
IF 7.497
Times Cited 10
C.elegans tm544 tm659