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

EMBO Rep. 2015 Mar;16(3):332-40. doi: 10.15252/embr.201439123. Epub 2015 Feb 4.

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.

Keywords: AAA+ ATPase; UPR; proteostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Caenorhabditis elegans Proteins
  • Cell Cycle Proteins
  • Repressor Proteins
  • Adenosine Triphosphatases
  • RUVB-2 protein, C elegans
  • Valosin Containing Protein