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

What is it about?

These days, many members of aminoacyl-tRNA synthetases (ARS) including glutamyl-prolyl-tRNA-synthetase (EPRS) are being shown to have disease-related functions more than traditional roles in protein translational process. One of the pathological roles of EPRS can be based on the fact that anti-fibrotic reagent, halofuginone, targets against EPRS, although halofuginone and its derivatives show significant side effects, presumably because the mechanistic aspects of how EPRS is involved in the regulation of fibrotic phenotypes are more than its tRNA charging activity. Furthermore, mechanisms of anti-fibrotic halofuginone to target prolyl-tRNA synthetase (PRS) remain too-broadly unidentified. Identification of mode of actions by halofuginone and reletives on the EPRS activity should have included the understanding of how EPRS causes fibrotic phenotypes. Since abnormal expression and deposition of extracellular matrix (ECM) can be the main characteristics of liver fibrosis, the roles of EPRS in ECM expression may be more than its proline-charging of tRNAs during translational process. Interestingly in this study, we found that a traditional molecule for protein translation, EPRS could regulate the transcriptional induction of ECMs; EPRS regulated mRNA levels of ECMs. EPRS formed signaling complex consisting of TGFbeta1R, SMAD3, JAKs, and STAT6, during ECM production. Thus, EPRS can be importantly involved in the TGFbeta1-mediated induction of ECMs via STAT6-mediated transcriptional regulation of the molecules. Therefore, specific targeting TGFbeta1R/EPRS/STAT6 signaling axis can allow a safer anti-fibrotic strategy.

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