GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1.

Autor: Almada LL; Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA., Barroso K; Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA; INSERM U1242, 'Oncogenesis, Stress, Signaling', Université de Rennes, Rennes, France; Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France., Sen S; Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA., Toruner M; Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA., Sigafoos AN; Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA., Raja Arul GL; Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA., Pease DR; Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA., Vera RE; Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA., Olson RLO; Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA., Auner HW; Imperial College London, London, UK., Pedeux R; INSERM U1242, 'Oncogenesis, Stress, Signaling', Université de Rennes, Rennes, France; Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France., Iovanna JL; Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France., Chevet E; INSERM U1242, 'Oncogenesis, Stress, Signaling', Université de Rennes, Rennes, France; Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France. Electronic address: eric.chevet@inserm.fr., Fernandez-Zapico ME; Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address: fernandezzapico.martin@mayo.edu.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Gene regulatory mechanisms [Biochim Biophys Acta Gene Regul Mech] 2023 Jun; Vol. 1866 (2), pp. 194924. Date of Electronic Publication: 2023 Feb 25.
DOI: 10.1016/j.bbagrm.2023.194924
Abstrakt: 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.
Competing Interests: Declaration of competing interest EC is a founding member of Thabor Tx (https://www.thabor-tx.com/). The other authors declare that they have no competing interests with the contents of this article.
(Copyright © 2023. Published by Elsevier B.V.)
Databáze: MEDLINE
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