Glutamyl-prolyl-tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms

Dae Geun Song, Doyeun Kim, Jae Woo Jung, Seo Hee Nam, Ji Eon Kim, Hye Jin Kim, Jong Hyun Kim, Seo Jin Lee, Cheol Ho Pan, Sunghoon Kim, Jung Weon Lee

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16 Citations (Scopus)


Fibrosis is characterized by the increased accumulation of extracellular matrix (ECM), which drives abnormal cell proliferation and progressive organ dysfunction in many inflammatory and metabolic diseases. Studies have shown that halofuginone, a racemic halogenated derivative, inhibits glutamyl-prolyl-transfer RNA-synthetase (EPRS)-mediated fibrosis. However, the mechanism by which this occurs is unclear. We explored the mechanistic aspects of how EPRS could develop liver fibrotic phenotypes in cells and animal models. Treatment with TGF-β1 up-regulated fibronectin and collagen I levels in LX2 hepatic stellate cells. This effect was inhibited in prolyl-transfer RNA synthetase (PRS)-suppressed LX2 cells. Using the promoter luciferase assay, TGF-β1–mediated collagen I, α1 chain transcription and γ2 basal laminin transcription in LX2 cells were down-regulated by EPRS suppression, suggesting that EPRS may play roles in ECM production at transcriptional levels. Furthermore, signal transducer and activator of transcription (STAT) signaling activation was involved in the effects of TGF-β1 on ECM expression in a PRS-dependent manner. This was mediated via a protein-protein complex formation consisting of TGF-β1 receptor, EPRS, Janus kinases, and STAT6. Additionally, ECM expression in fibrotic livers overlapped with EPRS expression along fibrotic septa regions and was positively correlated with STAT6 activation in carbon tetrachloride-treated mice. This was less obvious in livers of Eprs−/+ mice. These findings suggest that, during fibrosis development, EPRS plays roles in nontranslational processes of ECM expression via intracellular signaling regulation upon TGF-β1 stimulation.—Song, D.-G., Kim, D., Jung, J. W., Nam, S. H., Kim, J. E., Kim, H.-J., Kim, J. H., Lee, S.-J., Pan, C.-H., Kim, S., Lee, J. W. Glutamyl-prolyl-tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms. FASEB J. 33, 4341–4354 (2019).

Original languageEnglish
Pages (from-to)4341-4354
Number of pages14
JournalFASEB Journal
Issue number3
Publication statusPublished - 2019 Mar 1

Bibliographical note

Funding Information:
The authors thank Dr. Myung Hee Kim (Korea Research Institute of Bioscience and Biotechnology) for EPRS constructs, Dr. Scott Friedman (Ichan School of Medicine, Mount Sinai, New York, NY, USA) for LX2 cells, and Dr. Jin Ho Chung (Seoul National University) for HFFs. This work was supported by Korea Institute of Science and Technology Gangneung Institute Intramural Research Grant 2Z05310 (to C.-H.P. and D.-G.S.); Basic Science Research Program through the National Research Foundation of Korea (NRF) (funded by the Ministry of Science); Information and Communications Technology (ICT) and Future Planning Grants NRF-2018M3A9C8020027 and NRF-2017R1A2B3005015; Tumor Microenvironment Global Core Research Center (GCRC) Grant 2011-0030001; and Medicinal Bioconvergence Research Center Grant NRF-2013M3A6A4044019 (to J.W.L.). The authors declare no conflicts of interest.

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All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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