Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115.
Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458.
Proc Natl Acad Sci U S A. 2020 Apr 21;117(16):8900-8911. doi: 10.1073/pnas.1913788117. Epub 2020 Apr 6.
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.
感知氨基酸丰度的信号通路对于组织稳态和细胞防御至关重要。我们实验室之前已经表明，卤夫酮（HF）抑制谷氨酰-脯氨酰-tRNA 合成酶（EPRS）的脯氨酰-tRNA 合成酶催化活性，从而激活氨基酸反应（AAR）。我们现在表明，HF 处理选择性地抑制多种细胞类型中的炎症反应，并且这些治疗益处发生在缺乏 AAR 的标志性效应物 GCN2 的细胞中。从培养的成纤维样滑膜细胞中耗尽精氨酸、组氨酸或赖氨酸，可重现 HF 治疗的关键方面，而无需利用 GCN2 或哺乳动物雷帕霉素靶蛋白复合物 1 途径信号。与 HF 一样，苏氨酰-tRNA 合成酶抑制剂博来霉素抑制细胞因子刺激的成纤维样滑膜细胞中组织重塑和炎症介质的诱导，而无需 GCN2，但两种氨酰-tRNA 合成酶（aaRS）抑制剂对 GCN1 的去除均敏感。AAR 途径的上游成分 GCN1 结合到核糖体上，并且 GCN2 的激活是必需的。这些观察结果表明，与 AAR/GCN2 信号盒无关，aaRS 抑制剂（如 HF）可以调节炎症反应，并且 GCN1 具有与其激活 GCN2 不同的作用。我们提出 GCN1 参与了从经典 AAR 分支出来的先前未被认识到的氨基酸传感器途径。
