1. GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1
- Author
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Almada, Luciana L., Barroso, Kim, Sen, Sandhya, Törüner, Murat, Sigafoos, Ashley N, Raja Arul, Glancis L, Pease, David R, Vera, Renzo E., Olson, Rachel L O, Auner, Holger W, Pedeux, Rémy, Iovanna, Juan L, Chevet, Eric, Fernandez-Zapico, Martin E, Mayo Clinic [Rochester], Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Imperial College London, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was funded by grants from INSERM, Institut National du Cancer (INCa, PLBio 2017, 2019, 2020), Région Bretagne, Rennes Métropole, Fondation pour la recherche Médicale (FRM, DEQ20180339169), EU H2020 MSCA ITN-675448 (TRAINERS), la Ligue Contre le Cancer Comités d'Ille-et-Vilaine, des Côtes d'Armor et du Morbihan and MSCA RISE-734749 (INSPIRED) to EC and MEFZ was supported by NCI CA136526. KB was funded by a grant from la Ligue Contre le Cancer., and European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015)
- Subjects
Structural Biology ,p97/VCP ,GLI1 ,Genetics ,Biophysics ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,UPR ,USF2 ,ER stress ,Molecular Biology ,Biochemistry ,HDAC1 ,Hedgehog - Abstract
International audience; 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.
- Published
- 2023
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