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Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells
- Title
- Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells
- Authors
- Kim, Yeonjin; Sundrud, Mark S.; Zhou, Changqian; Edenius, Maja; Zocco, Davide; Powers, Kristen; Zhang, Miao; Mazitschek, Ralph; Rao, Anjana; Yeo, Chang-Yeol; Noss, Erika H.; Brenner, Michael B.; Whitman, Malcolm; Keller, Tracy L.
- Ewha Authors
- 여창열
- SCOPUS Author ID
- 여창열
- Issue Date
- 2020
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- ISSN
- 0027-8424
- Citation
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA vol. 117, no. 16, pp. 8900 - 8911
- Keywords
- halofuginone (HF); aminoacyl-tRNA synthetase (aaRS) inhibition; GCN2; GCN1; amino acid catabolism
- Publisher
- NATL ACAD SCIENCES
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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.
- DOI
- 10.1073/pnas.1913788117
- Appears in Collections:
- 자연과학대학 > 생명과학전공 > Journal papers
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