ArticleProceedings of the National Academy of Sciences of the United States of America2011
Dual role of methionyl-tRNA synthetase in the regulation of translation and tumor suppressor activity of aminoacyl-tRNA synthetase-interacting multifunctional protein-3.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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79 citing papers in PubMed, 120 citations in OpenAlex.
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- Allosteric disordering of eIF2B regulates the integrated stress response.Nature chemical biology · 2026Article
- Cryo-EM structure of the LARS1:IARS1 complex reveals a nutrient-responsive switch controlling mTORC1 signaling.Nature communications · 2026Article
- Variant-specific interaction of kinectin 1 with the multi-tRNA synthetase complex regulates ER sheet organization.iScience · 2026Article
- Methionyl-tRNA synthetase 1 expression, the possibility as a diagnostic and prognostic factor in papillary thyroid cancer.BMC cancer · 2025Article
- Methionyl-tRNA synthetase 1 participates in hepatocellular carcinoma and its regulated gene profile possesses potent prognostic ability.World journal of gastrointestinal oncology · 2025Article
- Hesperidin Suppressed Colorectal Cancer through Inhibition of Glycolysis.Chinese journal of integrative medicine · 2025Article
- The tumor-promoting role of methionyl-tRNA synthetase 1 in ovarian cancer and its potential mechanisms.Medical oncology (Northwood, London, England) · 2025Article
- NUFIP1 integrates amino acid sensing and DNA damage response to maintain the intestinal homeostasis.Nature metabolism · 2025Article
- The Integrated Stress Response in Pancreatic Development, Tissue Homeostasis, and Cancer.Gastroenterology · 2024Review
- The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.Molecular oncology · 2024Article
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- The GCN2/eIF2αK stress kinase regulates PP1 to ensure mitotic fidelity.EMBO reports · 2023Article
- MARS2 drives metabolic switch of non-small-cell lung cancer cells via interaction with MCU.Redox biology · 2023Article
- Multiple Roles of the Stress Sensor GCN2 in Immune Cells.International journal of molecular sciences · 2023Review
- Immunogenic cell death triggered by impaired deubiquitination in multiple myeloma relies on dysregulated type I interferon signaling.Frontiers in immunology · 2023Article
- Signaling plasticity in the integrated stress response.Frontiers in cell and developmental biology · 2023Review
- EPRS1 Controls the TGF-Molecular and cellular biology · 2023Article
- Glutamyl-prolyl-tRNA synthetase 1 coordinates early endosomal anti-inflammatory AKT signaling.Nature communications · 2022Article
19 more citing papers are in PubMed but not listed here.
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11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mammalian methionyl-tRNA synthetase (MRS) plays an essential role in initiating translation by transferring Met to initiator tRNA (tRNA(i)(Met)). MRS also provides a cytosolic anchoring site for aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3)/p18, a potent tumor suppressor that is translocated to the nucleus for DNA repair upon DNA damage. However, the mechanism by which this enzyme mediates these two seemingly unrelated functions is unknown. Here we demonstrate that AIMP3 is released from MRS by UV irradiation-induced stress. Dissociation was induced by phosphorylation of MRS at Ser662 by general control nonrepressed-2 (GCN2) following UV irradiation. Substitution of Ser662 to Asp (S662D) induced a conformational change in MRS and significantly reduced its interaction with AIMP3. This mutant possessed significantly reduced MRS catalytic activity because of loss of tRNA(Met) binding, resulting in down-regulation of global translation. According to the Met incorporation assay using stable HeLa cells expressing MRS S662A or eukaryotic initiation factor-2 subunit-α (eIF2α) S51A, inactivation of GCN2-induced phosphorylation at eIF2α or MRS augmented the role of the other, suggesting a cross-talk between MRS and eIF2α for efficient translational inhibition. This work reveals a unique mode of regulation of global translation as mediated by aminoacyl-tRNA synthetase, specifically MRS, which we herein identified as a previously unidentified GCN2 substrate. In addition, our research suggests a dual role for MRS: (i) as a coregulator with eIF2α for GCN2-mediated translational inhibition; and (ii) as a coupler of translational inhibition and DNA repair following DNA damage by releasing bound tumor suppressor AIMP3 for its nuclear translocation.
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