@article{865d85f642a74e12b339e7f24e848607,
title = "Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells",
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.",
keywords = "Amino acid catabolism, Aminoacyl-tRNA synthetase (aaRS) inhibition, GCN1, GCN2, Halofuginone (HF)",
author = "Yeonjin Kim and Sundrud, {Mark S.} and Changqian Zhou and Maja Edenius and Davide Zocco and Kristen Powers and Miao Zhang and Ralph Mazitschek and Anjana Rao and Yeo, {Chang Yeol} and Noss, {Erika H.} and Brenner, {Michael B.} and Malcolm Whitman and Keller, {Tracy L.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Thaddeus Carlson, Ivana Djuretic, and Radha Ramesh (Tempero Pharmaceuticals) for technical support for T cell experiments; Kamil Slowikowski (Broad Institute) for valuable advice and assistance with the analysis of RNA sequencing data; John Hutchinson (Harvard School of Public Health) for data analysis and figure preparation of transcriptomics in Fig. 1; and Fred Goldberg (Harvard Medical School) and Vicki Rosen (Harvard School of Dental Medicine) for critical reading of the manuscript. M.W. and T.L.K. were supported by Department of Defense Award W81XWH-15-1-0396, National Institute of Allergy and Infectious Diseases Grant AI142343, and an unrestricted research grant from Allied Bristol Life Sciences. M.S.S. was supported by The Scripps Research Institute Florida via the state of Florida. A.R. was supported by National Institute of Allergy and Infectious Diseases Grant AI128589. C.-Y.Y. was supported by the National Research Foundation of Korea grant funded by the Korea government (Grants 2012R1A5A1048236 and 2015R1A2A2A05027993). Funding Information: We thank Thaddeus Carlson, Ivana Djuretic, and Radha Ramesh (Tempero Pharmaceuticals) for technical support for T cell experiments; Kamil Slowikowski (Broad Institute) for valuable advice and assistance with the analysis of RNA sequencing data; John Hutchinson (Harvard School of Public Health) for data analysis and figure preparation of transcriptomics in Fig. 1; and Fred Goldberg (Harvard Medical School) and Vicki Rosen (Harvard School of Dental Medicine) for critical reading of the manuscript. M.W. and T.L.K. were supported by Department of Defense Award W81XWH-15-1-0396, National Institute of Allergy and Infectious Diseases Grant AI142343, and an unrestricted research grant from Allied Bristol Life Sciences. M.S.S. was supported by The Scripps Research Institute Florida via the state of Florida. A.R. was supported by National Institute of Allergy and Infectious Diseases Grant AI128589. C.-Y.Y. was supported by the National Research Foundation of Korea grant funded by the Korea government (Grants 2012R1A5A1048236 and 2015R1A2A2A05027993). Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = apr,
day = "21",
doi = "10.1073/pnas.1913788117",
language = "English",
volume = "117",
pages = "8900--8911",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "16",
}