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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01337

Glutamyl-Prolyl-tRNA Synthetase Regulates Epithelial Expression of Mesenchymal Markers and Extracellular Matrix Proteins: Implications for Idiopathic Pulmonary Fibrosis

 Dae-Geun Song1,  Doyeun Kim2, Jae Woo Jung3, Seo Hee Nam1, Ji Eon Kim1, Hye-Jin Kim1, Jong Hyun Kim2, Cheol-Ho Pan4*,  Sunghoon Kim2 and  Jung Weon Lee5*
  • 1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, South Korea
  • 2Medicinal Bioconvergence Research Center, Seoul National University, South Korea
  • 3Interdisciplinary Graduate Program in Genetic Engineering, Seoul National University, South Korea
  • 4Systems Biotechnology Research Center, Korea Institute of Science and Technology (KIST), South Korea
  • 5College of Pharmacy, Seoul National University, South Korea

Idiopathic pulmonary fibrosis (IPF), a chronic disease of unknown cause, is characterized by abnormal accumulation of extracellular matrix (ECM) in fibrotic foci in the lung. Previous studies have shown that the transforming growth factor b1 (TGFβ1) and signal transducers and activators of transcription (STAT) pathways play roles in IPF pathogenesis. Glutamyl-prolyl-tRNA-synthetase (EPRS) has been identified as a target for anti-fibrosis therapy, but the link between EPRS and TGFβ1-mediated IPF pathogenesis remains unknown. Here, we studied the role of EPRS in the development of fibrotic phenotypes in A549 alveolar epithelial cells and bleomycin-treated animal models. We found that EPRS knockdown inhibited the TGFβ1-mediated upregulation of fibronectin and collagen I and the mesenchymal proteins α-smooth muscle actin (α-SMA) and snail 1. TGFβ1-mediated transcription of collagen I-α1 and laminin γ2 in A549 cells was also down-regulated by EPRS suppression, indicating that EPRS is required for ECM protein transcriptions. Activation of STAT signaling in TGFβ1-induced ECM expression was dependent on EPRS. TGFβ1 treatment resulted in EPRS-dependent in vitro formation of a multi-protein complex consisting of the TGFβ1 receptor, EPRS, Janus tyrosine kinases (JAKs), and STATs. In vivo lung tissue from bleomycin-treated mice showed EPRS-dependent STAT6 phosphorylation and ECM production. Our results suggest that epithelial EPRS regulates the expression of mesenchymal markers and ECM proteins via the TGFβ1/STAT signaling pathway. Therefore, epithelial EPRS can be used as a potential target to develop anti-IPF treatments.

Keywords: Idiopathic pulmonary fibrosis (IPF), bleomycin fibrotic animal model, Extracellular Matrix (ECM), prolyl-tRNA-synthetase, Signal Transduction, STAT6

Received: 02 Aug 2018; Accepted: 30 Oct 2018.

Edited by:

Marc Diederich, Seoul National University, South Korea

Reviewed by:

Carole L. Wilson, Medical University of South Carolina, United States
Suresh K. Kalangi, Indrashil University, India  

Copyright: © 2018 Song, Kim, Jung, Nam, Kim, Kim, Kim, Pan, Kim and Lee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Cheol-Ho Pan, Systems Biotechnology Research Center, Korea Institute of Science and Technology (KIST), Gangneung-si, South Korea, panc@kist.re.kr
Prof. Jung Weon Lee, College of Pharmacy, Seoul National University, Seoul, South Korea, jwl@snu.ac.kr