p97/VCP induces GLI1 to control XBP1-dependent endoplasmic reticulum stress transcriptional response

Upon accumulation of improperly folded proteins in the ER, an adaptive pathway named the UPR is triggered to restore ER homeostasis. The induction of stress genes controlling ER dynamics is a condition sine qua non for an effective UPR. Although this requirement has been extensively characterized, the transcriptional mechanism underlying this process remains in part elucidated. Here, we show that p97/VCP, an AAA+ ATPase known to modulate ER stress-induced gene expression, dynamically interacts with RUVBL2 and the mSin3A-HDAC1/2 complex. Further analysis of the mechanism defined a novel interplay between the aforementioned molecules and the transcription factor USF2 to control expression of GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal conditions, GLI1 is repressed by RUVBL2-mSin3A-HDAC1/2 while upon ER stress GLI1 is induced through a mechanism requiring p97/VCP-mediated extraction of the repressor complex. Further analysis showed that GLI1 cooperate with ATF6f to activate the expression of XBP1, a transcription factor regulating the expression of genes controlling cellular stress response, under ER conditions. Overall, our work demonstrates that p97/VCP orchestrates the activation of GLI1 upon ER stress in a Hh ligand-independent fashion and defines the interplay between the newly identified p97/VCP-mSin3A-HDAC1/2 complex and the transcription factor USF2 as an essential player in this process.