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Harvard School of Dental Medicine

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Proc. Natl. Acad. Sci. USA, First published April 6, 2020 | https://doi.org/10.1073/pnas.1913788117 Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells

Yeonjin Kim^a,1, Mark S. Sundrud^b,1, Changqian Zhou^a, Maja Edenius^a, Davide Zocco^a, Kristen Powers^a, Miao Zhang^a, Ralph Mazitschek^c, Anjana Rao^d, Chang-Yeol Yeo^e, Erika H. Noss^f,g, Michael B. Brenner^f,2, Malcolm Whitman^a,2, and Tracy L. Keller^a,2

^aDepartment of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115; ^bDepartment of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458; ^cCenter for Systems Biology, Massachusetts General Hospital, Boston, MA 02114; ^dDivision of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037; ^eDepartment of Life Science, Division of Life and Pharmaceutical Sciences, Ewha Womans University, 03760 Seoul, Korea; ^fBrigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and ^gDivision of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195

¹Y.K. and M.S.S. contributed equally to this work.
²To whom correspondence may be addressed.

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.

halofuginone (HF), aminoacyl-tRNA synthetase (aaRS) inhibition, GCN2, GCN1, amino acid catabolism

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형식Research article
게재일2020년 04월 (BRIC 등록일 2020-04-21)
연구진국내+국외 연구진
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