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

Abstract

© 2015 The Authors. 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. Synopsis During ER stress, p97/CDC-48 mediates reptin degradation thereby enabling both ATF6 activation and XBP1 mRNA splicing. This work uncovers another layer in the regulation of canonical ER stress signaling. p97/CDC-48 induces reptin degradation upon ER stress. Reptin is a repressor of both ATF6 activation and XBP1 mRNA splicing. p97/cdc-48-mediated retpin degradation promotes ER adaptive response to stress. During ER stress, p97/CDC-48 mediates reptin degradation thereby enabling both ATF6 activation and XBP1 mRNA splicing. This work uncovers another layer in the regulation of canonical ER stress signaling.