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Genome‐wide screen identifies a novel p97/ CDC ‐48‐dependent pathway regulating ER ‐stress‐induced gene transcription
Author(s) -
Marza Esther,
Taouji Saïd,
Barroso Kim,
Raymond AnneAurélie,
Guignard Léo,
Bonneu Marc,
PallaresLupon Néstor,
Dupuy JeanWilliam,
FernandezZapico Martin E,
Rosenbaum Jean,
Palladino Francesca,
Dupuy Denis,
Chevet Eric
Publication year - 2015
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201439123
Subject(s) - endoplasmic reticulum , biology , genetics
The accumulation of misfolded proteins in the endoplasmic reticulum ( ER ) activates the Unfolded Protein Response ( UPR ER ) to restore ER homeostasis. The AAA + ATP ase 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 RNA i screen in combination with quantitative proteomic analysis in C aenorhabditis elegans, we have identified RUVB ‐2, a AAA + ATP ase, 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 XBP 1‐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.