Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells
- 주제(키워드) halofuginone (HF) , aminoacyl-tRNA synthetase (aaRS) inhibition , GCN2 , GCN1 , amino acid catabolism
- 주제(기타) Multidisciplinary Sciences
- 설명문(일반) [Kim, Yeonjin; Zhou, Changqian; Edenius, Maja; Zocco, Davide; Powers, Kristen; Zhang, Miao; Whitman, Malcolm; Keller, Tracy L.] Harvard Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA; [Sundrud, Mark S.] Scripps Res Inst, Dept Immunol & Microbiol, Jupiter, FL 33458 USA; [Mazitschek, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA; [Rao, Anjana] La Jolla Inst Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA; [Yeo, Chang-Yeol] Ewha Womans Univ, Div Life & Pharmaceut Sci, Dept Life Sci, Seoul 03760, South Korea; [Noss, Erika H.; Brenner, Michael B.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA; [Noss, Erika H.] Univ Washington, Dept Med, Div Rheumatol, Seattle, WA 98195 USA
- 등재 SCIE, SCOPUS
- OA유형 Bronze, Green Published
- 발행기관 NATL ACAD SCIENCES
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000168761
- 본문언어 영어
- Published As https://dx.doi.org/10.1073/pnas.1913788117
- PubMed https://pubmed.ncbi.nlm.nih.gov/32253314
초록/요약
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.
more