Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription
Marza E., Taouji S., Barroso K., Raymond A.-A., Guignard L., Bonneu M., Pallares-Lupon N., Dupuy J.-W., Fernandez-Zapico M., Rosenbaum J., Palladino F., Dupuy D., Chevet E.
3 févr. 2015
The accumulation of misfolded proteins in the endoplasmic reticulum (ER ) activates the Unfolded Protein Response (UPRER ) 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 UPRER 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 UPRER 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 UPRER 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.