ArticleProceedings of the National Academy of Sciences of the United States of America2020
Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 39 citations in OpenAlex.
- Extracellular vesicles derived by hypoxic preconditioned EPCs attenuated atherosclerosis by suppressing ferroptosis via regulating arginine metabolism.Redox biology · 2026Article
- tRNA synthetase activity is required for stress granule and P-body assembly.Genes & development · 2026Article
- Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).International journal of molecular medicine · 2026Review
- Differential cell survival outcomes in response to diverse amino acid stress.Life science alliance · 2025Article
- Review
- Highly expressed GCN1 is associated with cancer progression and poor prognosis in hepatocellular carcinoma patients.Cancer cell international · 2025Article
- Another Notch in the Belt of Rheumatoid Arthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2024Review
- Emerging Role of GCN1 in Disease and Homeostasis.International journal of molecular sciences · 2024Review
- DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis.Diabetes & metabolism journal · 2024Article
- Transfer RNAs as dynamic and critical regulators of cancer progression.Nature reviews. Cancer · 2023Review
- Immune priming in plants: from the onset to transgenerational maintenance.Essays in biochemistry · 2022Review
- Cellular responses to halofuginone reveal a vulnerability of the GCN2 branch of the integrated stress response.The EMBO journal · 2022Article
- MIRO2 Regulates Prostate Cancer Cell Growth via GCN1-Dependent Stress Signaling.Molecular cancer research : MCR · 2022Article
- Inducible SystemicInternational journal of molecular sciences · 2022Article
- Understanding the role of cysteine in ferroptosis: progress & paradoxes.The FEBS journal · 2022Article
- Orally Administered Halofuginone-Loaded TPGS Polymeric Micelles Against Triple-Negative Breast Cancer: Enhanced Absorption and Efficacy with Reduced Toxicity and Metastasis.International journal of nanomedicine · 2022Article
- The effects of graded calorie restriction XVII: Multitissue metabolomics reveals synthesis of carnitine and NAD, and tRNA charging as key pathways.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Metabolic and behavioral features of acute hyperpurinergia and the maternal immune activation mouse model of autism spectrum disorder.PloS one · 2021Article
- A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis.Biochemistry. Biokhimiia · 2020Review
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Authors and funding
14 authors at 6 institutions in 2 countries.
Funding
Abstract
Signaling pathways that sense amino acid abundance are integral to tissue homeostasis and cellular defense. Our laboratory has previously shown that halofuginone (HF) inhibits the prolyl-tRNA synthetase catalytic activity of glutamyl-prolyl-tRNA synthetase (EPRS), thereby activating the amino acid response (AAR). We now show that HF treatment selectively inhibits inflammatory responses in diverse cell types and that these therapeutic benefits occur in cells that lack GCN2, the signature effector of the AAR. Depletion of arginine, histidine, or lysine from cultured fibroblast-like synoviocytes recapitulates key aspects of HF treatment, without utilizing GCN2 or mammalian target of rapamycin complex 1 pathway signaling. Like HF, the threonyl-tRNA synthetase inhibitor borrelidin suppresses the induction of tissue remodeling and inflammatory mediators in cytokine-stimulated fibroblast-like synoviocytes without GCN2, but both aminoacyl-tRNA synthetase (aaRS) inhibitors are sensitive to the removal of GCN1. GCN1, an upstream component of the AAR pathway, binds to ribosomes and is required for GCN2 activation. These observations indicate that aaRS inhibitors, like HF, can modulate inflammatory response without the AAR/GCN2 signaling cassette, and that GCN1 has a role that is distinct from its activation of GCN2. We propose that GCN1 participates in a previously unrecognized amino acid sensor pathway that branches from the canonical AAR.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.