Abstract |
Glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is known to associated with fibrosis through its catalytic activity to produce prolyl- tRNA. Although its catalytic inhibitor halofuginone (HF) has been known to inhibit the TGF-β pathway as well as to reduce prolyl- tRNA production for the control of fibrosis, the underlying mechanism how EPRS1 regulates the TGF-β pathway was not fully understood. Here, we show a noncatalytic function of EPRS1 in controlling the TGF-β pathway and hepatic stellate cell activation via its interaction with TGF-β receptor I (TβRI). Upon stimulation with TGF-β, EPRS1 is phosphorylated by TGF-β-activated kinase 1 (TAK1), leading to its dissociation from the multi- tRNA synthetase complex and subsequent binding with TβRI. This interaction increases the association of TβRI with SMAD2/3 while decreases that of TβRI with SMAD7. Accordingly, EPRS1 stabilizes TβRI by preventing the ubiquitin-mediated degradation of TβRI. HF disrupts the interaction between EPRS1 and TβRI, and reduces TβRI protein levels, leading to inhibition of the TGF-β pathway. In conclusion, this work suggests the novel function of EPRS1 involved in the development of fibrosis by regulating the TGF-β pathway and the antifibrotic effects of HF by controlling both of EPRS1 functions.
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Authors | Ina Yoon, Ji Ae Song, Ji Hun Suh, Sulhee Kim, Jonghyeon Son, Jong Hyun Kim, Song Yee Jang, Kwang Yeon Hwang, Myung Hee Kim, Sunghoon Kim |
Journal | Molecular and cellular biology
(Mol Cell Biol)
Vol. 43
Issue 5
Pg. 223-240
( 2023)
ISSN: 1098-5549 [Electronic] United States |
PMID | 37154023
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Receptor, Transforming Growth Factor-beta Type I
- Receptors, Transforming Growth Factor beta
- Transforming Growth Factor beta
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Topics |
- Humans
- Hepatic Stellate Cells
(metabolism)
- Receptor, Transforming Growth Factor-beta Type I
(metabolism)
- Receptors, Transforming Growth Factor beta
(genetics, metabolism)
- Transforming Growth Factor beta
(metabolism)
- Fibrosis
- Signal Transduction
(physiology)
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