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J Mol Med (Berl). 2019 Apr 26. doi: 10.1007/s00109-019-01787-9. [Epub ahead of print]

Regulation and role of the ER stress transcription factor CHOP in alveolar epithelial type-II cells.

Author information

1
Department of Internal Medicine, Justus-Liebig-University Giessen, Klinikstrasse 36, 35392, Giessen, Germany.
2
German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC), 35392, Giessen, Germany.
3
Excellence Cluster Cardiopulmonary System (ECCPS), 35392, Giessen, Germany.
4
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91, Stockholm, Sweden.
5
Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
6
Department of Internal Medicine, Justus-Liebig-University Giessen, Klinikstrasse 36, 35392, Giessen, Germany. Andreas.Guenther@innere.med.uni-giessen.de.
7
German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC), 35392, Giessen, Germany. Andreas.Guenther@innere.med.uni-giessen.de.
8
Excellence Cluster Cardiopulmonary System (ECCPS), 35392, Giessen, Germany. Andreas.Guenther@innere.med.uni-giessen.de.
9
European IPF Network and European IPF Registry, Giessen, Germany. Andreas.Guenther@innere.med.uni-giessen.de.
10
Agaplesion Lung Clinic Waldhof-Elgershausen, 35753, Greifenstein, Germany. Andreas.Guenther@innere.med.uni-giessen.de.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by type-II alveolar epithelial cell (AECII) injury and fibroblast hyperproliferation. Severe AECII endoplasmic reticulum (ER) stress is thought to underlie IPF, but is yet incompletely understood. We studied the regulation of C/EBP homologous protein (CHOP), a proapoptotic ER-stress-related transcription factor (TF) in AECII-like cells. Interestingly, single or combined overexpression of the active ER stress transducers activating transcription factor-4 (Atf4) and activating transcription factor-6 (p50Atf6) or spliced x-box-binding protein-1 (sXbp1) in MLE12 cells did not result in a substantial Chop induction, as compared to the ER stress inducer thapsigargin. Employing reporter gene assays of distinct CHOP promoter fragments, we could identify that, next to the conventional amino acid (AARE) and ER stress response elements (ERSE) within the CHOP promoter, activator protein-1 (AP-1) and c-Ets-1 TF binding sites are necessary for CHOP induction. Serial deletion and mutation analyses revealed that both AP-1 and c-Ets-1 motifs act in concert to induce CHOP expression. In agreement, CHOP promoter activity was greatly enhanced upon combined versus single overexpression of AP-1 and c-Ets-1. Moreover, combined overexpression of AP-1 and c-Ets-1 in MLE12 cells alone in the absence of any other ER stress inducer was sufficient to induce Chop protein expression. Further, AP-1 and c-Ets-1 were upregulated in AECII under ER stress conditions and in human IPF. Finally, Chop overexpression in vitro resulted in AECII apoptosis, lung fibroblast proliferation, and collagen-I production. We propose that CHOP activation by AP-1 and c-Ets-1 plays a key role in AECII maladaptive ER stress responses and consecutive fibrosis, offering new therapeutic prospects in IPF. KEY MESSAGES: Overexpression of active ER stress sensors Atf4, Atf6, and Xbp1 does not induce Chop. AP-1 and c-Ets-1 TFs are necessary for induction of the ER stress factor Chop. AP-1 and c-Ets-1 alone induce Chop expression in the absence of any ER stress inducers. AP-1 and c-Ets-1 are induced in AECII under ER stress conditions and in human IPF. Chop expression alone triggers AECII apoptosis and consecutive profibrotic responses.

KEYWORDS:

Activator protein-1 (AP-1); C/EBP homologous protein (CHOP); Endoplasmic reticulum (ER) stress; Protein c-Ets-1; Transcriptional regulation; Type-II alveolar epithelial cells (AECII)

PMID:
31025089
DOI:
10.1007/s00109-019-01787-9

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