Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells
| Autor: | Malcolm Whitman, Yeon Jin Kim, Davide Zocco, Kristen Powers, Tracy Keller, Erika H. Noss, Chang Yeol Yeo, Mark S. Sundrud, Maja Edenius, Ralph Mazitschek, Changqian Zhou, Anjana Rao, Miao Zhang, Michael B. Brenner |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Arginine
Primary Cell Culture Lysine Anti-Inflammatory Agents mTORC1 Mechanistic Target of Rapamycin Complex 1 Protein Serine-Threonine Kinases Cell Line Amino Acyl-tRNA Synthetases Arthritis Rheumatoid Mice chemistry.chemical_compound Piperidines Human Umbilical Vein Endothelial Cells Animals Humans RNA-Seq Amino Acids Lung Tissue homeostasis Quinazolinones Mice Knockout chemistry.chemical_classification Multidisciplinary Chemistry Aminoacyl tRNA synthetase Effector Synovial Membrane RNA-Binding Proteins Fibroblasts Biological Sciences Synoviocytes Amino acid Cell biology Gene Knockdown Techniques Trans-Activators Signal transduction Signal Transduction |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1913788117 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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