GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1. Almada, L. L., Barroso, K., Sen, S., Toruner, M., Sigafoos, A. N., Raja Arul, G. L., Pease, D. R., Vera, R. E., Olson, R. L. O., Auner, H. W., Pedeux, R., Iovanna, J. L., Chevet, E., & Fernandez-Zapico, M. E. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1866(2):194924, June, 2023. ![GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1 [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Upon accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER), the Unfolded Protein Response (UPR) is triggered to restore ER homeostasis. The induction of stress genes is a sine qua non condition for effective adaptive UPR. Although this requirement has been extensively described, the mechanisms underlying this process remain in part uncharacterized. Here, we show that p97/VCP, an AAA+ ATPase known to contribute to ER stress-induced gene expression, regulates the transcription factor GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal (non-ER stress) conditions, GLI1 is repressed by a p97/VCP-HDAC1 complex while upon ER stress GLI1 is induced through a mechanism requiring both USF2 binding and increase histone acetylation at its promoter. Interestingly, the induction of GLI1 was independent of ligand-regulated Hh signaling. Further analysis showed that GLI1 cooperates with ATF6f to induce promoter activity and expression of XBP1, a key transcription factor driving UPR. Overall, our work demonstrates a novel role for GLI1 in the regulation of ER stress gene expression and defines the interplay between p97/VCP, HDAC1 and USF2 as essential players in this process.
@article{almada_gli1_2023,
title = {{GLI1}, a novel target of the {ER} stress regulator p97/{VCP}, promotes {ATF6f}-mediated activation of {XBP1}},
volume = {1866},
issn = {1874-9399},
url = {https://www.sciencedirect.com/science/article/pii/S1874939923000196},
doi = {10.1016/j.bbagrm.2023.194924},
abstract = {Upon accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER), the Unfolded Protein Response (UPR) is triggered to restore ER homeostasis. The induction of stress genes is a sine qua non condition for effective adaptive UPR. Although this requirement has been extensively described, the mechanisms underlying this process remain in part uncharacterized. Here, we show that p97/VCP, an AAA+ ATPase known to contribute to ER stress-induced gene expression, regulates the transcription factor GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal (non-ER stress) conditions, GLI1 is repressed by a p97/VCP-HDAC1 complex while upon ER stress GLI1 is induced through a mechanism requiring both USF2 binding and increase histone acetylation at its promoter. Interestingly, the induction of GLI1 was independent of ligand-regulated Hh signaling. Further analysis showed that GLI1 cooperates with ATF6f to induce promoter activity and expression of XBP1, a key transcription factor driving UPR. Overall, our work demonstrates a novel role for GLI1 in the regulation of ER stress gene expression and defines the interplay between p97/VCP, HDAC1 and USF2 as essential players in this process.},
number = {2},
urldate = {2023-11-29},
journal = {Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms},
author = {Almada, Luciana L. and Barroso, Kim and Sen, Sandhya and Toruner, Murat and Sigafoos, Ashley N. and Raja Arul, Glancis L. and Pease, David R. and Vera, Renzo E. and Olson, Rachel L. O. and Auner, Holger W. and Pedeux, Rémy and Iovanna, Juan L. and Chevet, Eric and Fernandez-Zapico, Martin E.},
month = jun,
year = {2023},
keywords = {ER stress, GLI1, HDAC1, Hedgehog, UPR, USF2, p97/VCP},
pages = {194924},
}
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Although this requirement has been extensively described, the mechanisms underlying this process remain in part uncharacterized. Here, we show that p97/VCP, an AAA+ ATPase known to contribute to ER stress-induced gene expression, regulates the transcription factor GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal (non-ER stress) conditions, GLI1 is repressed by a p97/VCP-HDAC1 complex while upon ER stress GLI1 is induced through a mechanism requiring both USF2 binding and increase histone acetylation at its promoter. Interestingly, the induction of GLI1 was independent of ligand-regulated Hh signaling. Further analysis showed that GLI1 cooperates with ATF6f to induce promoter activity and expression of XBP1, a key transcription factor driving UPR. 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