Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2

Nat Cell Biol. 2023 Apr;25(4):592-603. [ PMID: 37237245 ]

Inflammation alters metabolite levels, and arginine is one metabolite with a well-established role in immune responses. Aminoacyl-tRNA synthetases catalyze the first step of protein synthesis but can also participate in cell signaling. In this study, depleting arginine during inflammation lowered the amount of nuclear arginyl-tRNA synthetase (ArgRS). Surprisingly, nuclear ArgRS interacts with and co-localizes with SRRM2, a spliceosomal and nuclear speckle protein. Reduced nuclear ArgRS correlated with changes in condensate-like nuclear trafficking of SRRM2 and with altered splice-site usage in selected genes. These splicing shifts produced different protein isoforms that changed cellular metabolism and peptide presentation to immune cells. The findings reveal a mechanism by which an aminoacyl-tRNA synthetase for a metabolically controlled amino acid tunes the splicing machinery during inflammation.

Prolyl-tRNA synthetase inhibitor as a novel first-in-class keloid treatment: downregulation of de novo collagen synthesis and inflammatory cascade

Br J Dermatol. 2025 Jul 17;193(2):298-309. [ PMID: 40233147 ]

Keloids are fibrotic skin lesions caused by excessive collagen deposition, and current treatments relapse frequently. The investigators reasoned that blocking proline, an amino acid essential for collagen production, could offer a more fundamental approach. They developed DWN12088, which downregulates prolyl-tRNA synthetase (PRS). PRS was overexpressed in patient-derived keloid fibroblasts and keloid tissue. A selective PRS inhibitor lowered fibrotic markers, reduced cell migration, and cut collagen production in keloid fibroblasts, and it suppressed keloid formation in a xenograft SCID mouse model while mitigating inflammation and fibrosis. DWN12088 may therefore be a first-in-class therapy that prevents keloid development, pending clinical validation.

Glutamyl-prolyl-tRNA synthetase (EPRS1) drives tubulointerstitial nephritis-induced fibrosis by enhancing T cell proliferation and activity

Kidney Int. 2024 May;105(5):997-1019. [ PMID: 38320721 ]

Toxin- and drug-induced tubulointerstitial nephritis (TIN) often progresses to irreversible fibrosis that requires dialysis. This study asked whether glutamyl-prolyl-tRNA synthetase 1 (EPRS1), the enzyme that charges glutamic acid and proline onto tRNAs, modulates immune cells in TIN. After inducing TIN with an adenine-mixed diet, the kidneys showed infiltration of EPRS1-high T cells, particularly proliferating T and gamma-delta T cells. Eprs1+/- mice had less CD4+ and CD8+ T cell proliferation, lower IL-17 production by gamma-delta T cells, and reduced fibrosis. The EPRS1-targeting small molecule bersiporocin, already in clinical trials for idiopathic pulmonary fibrosis, alleviated immunofibrotic aggravation in TIN. High EPRS1 in human kidney tissue and blood T cells predicted worse outcomes, positioning EPRS1 as a therapeutic target in TIN.

tRNA Charging Sequencing

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