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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, YeonjinSundrud, Mark S.Zhou, ChangqianEdenius, MajaZocco, DavidePowers, KristenZhang, MiaoMazitschek, RalphRao, AnjanaYeo, Chang-YeolNoss, Erika H.Brenner, Michael B.Whitman, MalcolmKeller, Tracy L.
Ewha Authors
여창열
SCOPUS Author ID
여창열scopus
Issue Date
2020
Journal Title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN
0027-8424JCR Link
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) inhibitionGCN2GCN1amino acid catabolism
Publisher
NATL ACAD SCIENCES
Indexed
SCIE; SCOPUS WOS 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
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자연과학대학 > 생명과학전공 > Journal papers
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