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Geranylgeranyl diphosphate synthase deficiency aggravates lung fibrosis in mice by modulating TGF-β1/BMP-4 signaling

  • Meizi Chen , Bing Wan , Suhua Zhu , Fang Zhang , Jiajia Jin , Xinying Li , Xianghai Wang , Yanling Lv , Cen Chen , Tangfeng Lv and Yong Song EMAIL logo
Published/Copyright: May 23, 2019
Biological Chemistry
From the journal Biological Chemistry Volume 400 Issue 12

Abstract

Geranylgeranyl diphosphate synthase (GGPPS) is an enzyme that catalyzes the synthesis of geranylgeranyl pyrophosphate (GGPP). GGPPS is implicated in many disorders, but its role in idiopathic pulmonary fibrosis (IPF) remains unclear. This study aimed to investigate the role of GGPPS in IPF. We established bleomycin-induced lung injury in a lung-specific GGPPS-deficient mouse (GGPPS−/−) and detected GGPPS expression in lung tissues by Western blot and immunohistochemistry analysis. We found that GGPPS expression increased during lung injury and fibrosis in mice induced by bleomycin, and GGPPS deficiency augmented lung fibrosis. GGPPS deficiency activated lung fibroblast by facilitating transforming growth factor β1 while antagonizing bone morphogenetic protein 4 signaling. Notably, the supplementation of exogenous GGPP mitigated lung fibrosis in GGPPS−/− mice induced by bleomycin. In conclusion, our findings suggest that GGPPS provides protection against pulmonary fibrosis and that the restoration of protein geranylgeranylation may benefit statin-induced lung injury.

Keywords: bone morphogenetic protein (BMP-4); geranylgeranyl diphosphate synthase; lung fibrosis; transforming growth factor beta 1 (TGF-β1)

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: 81770082

Funding source: Jiangsu Provincial Key Research and Development Program

Award Identifier / Grant number: BE2016721

Funding statement: This work was supported by the National Natural Science Foundation of China (Funder Id: http://dx.doi.org/10.13039/501100001809, no. 81770082) and the Jiangsu Provincial Key Research and Development Program (no. BE2016721).

  1. Authors’ contributions: All authors reviewed the manuscript and provided comments or suggestions. All authors read and approved the final manuscript.

  2. Competing interests: All authors declared no conflicts of interest.

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Received: 2019-02-26
Accepted: 2019-05-12
Published Online: 2019-05-23
Published in Print: 2019-12-18

©2019 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/hsz-2019-0168
Keywords for this article
bone morphogenetic protein (BMP-4); geranylgeranyl diphosphate synthase; lung fibrosis; transforming growth factor beta 1 (TGF-β1)

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Recent advances in the development of legumain-selective chemical probes and peptide prodrugs
  4. Genes and Nucleic Acids
  5. Research Articles/Short Communications
  6. Tauroursodeoxycholate protects from glycochenodeoxycholate-induced gene expression changes in perfused rat liver
  7. Protein Structure and Function
  8. Comparative studies of Aspergillus fumigatus 2-methylcitrate synthase and human citrate synthase
  9. Assessment of the denaturation of collagen protein concentrates using different techniques
  10. Membranes, Lipids, Glycobiology
  11. Red blood cells participate in reverse cholesterol transport by mediating cholesterol efflux of high-density lipoprotein and apolipoprotein A-I from THP-1 macrophages
  12. Molecular Medicine
  13. A transgenic zebrafish model of hepatocyte function in human Z α1-antitrypsin deficiency
  14. Cell Biology and Signaling
  15. Geranylgeranyl diphosphate synthase deficiency aggravates lung fibrosis in mice by modulating TGF-β1/BMP-4 signaling
  16. Proteolysis
  17. The lysosomal aminopeptidase tripeptidyl peptidase 1 displays increased activity in malignant pancreatic cysts
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