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

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.