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.

journal_name

EMBO Rep

journal_title

EMBO reports

authors

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

doi

10.15252/embr.201439123

subject

Has Abstract

pub_date

2015-03-01 00:00:00

pages

332-40

issue

3

eissn

1469-221X

issn

1469-3178

pii

embr.201439123

journal_volume

16

pub_type

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