EPRS1 Controls the TGF-β Signaling Pathway via Interaction with TβRI in Hepatic Stellate Cell

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-beta pathway as well as to reduce prolyl-tRNA production for the control of fibrosis, the underlying mechanism how EPRS1 regulates the TGF-beta pathway was not fully understood. Here, we show a noncatalytic function of EPRS1 in controlling the TGF-beta pathway and hepatic stellate cell activation via its interaction with TGF-beta receptor I (T beta RI). Upon stimulation with TGF-beta, EPRS1 is phosphorylated by TGF-beta-activated kinase 1 (TAK1), leading to its dissociation from the multi-tRNA synthetase complex and subsequent binding with T beta RI. This interaction increases the association of T beta RI with SMAD2/3 while decreases that of T beta RI with SMAD7. Accordingly, EPRS1 stabilizes T beta RI by preventing the ubiquitin-mediated degradation of T beta RI. HF disrupts the interaction between EPRS1 and T beta RI, and reduces T beta RI protein levels, leading to inhibition of the TGF-beta pathway. In conclusion, this work suggests the novel function of EPRS1 involved in the development of fibrosis by regulating the TGF-beta pathway and the antifibrotic effects of HF by controlling both of EPRS1 functions.