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.

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The T-box gene VegT plays a crucial role during mesendoderm specification of the amphibian embryo. While the function of maternal VegT (mVegT) has been extensively investigated, little is known about the function and transcriptional regulation of zygotic VegT (zVegT). In the present study, we used comparative genomics and a knockdown experiment to demonstrate that zVegT is the orthologous gene of zebrafish Spadetail/Tbx16 and chick Tbx6L/Tbx6, and has an essential role in paraxial mesodermal formation. zVegT knockdown embryos show several defects in the patterning of trunk mesoderm, such as abnormal segmentation of somites, a reduction in muscle, and the formation of an abnormal mass of cells at the tail tip. We also identified the cis-regulatory elements of zVegT that are necessary and sufficient for mesodermspecific expression. These cis-regulatory elements are located in two separate upstream regions of zVegT, corresponding to the first intron of mVegT. The results of in vitro binding and functional assays indicate that Forkhead box H1 (FoxH1) and Eomesodermin (Eomes) are the trans-acting factors required for zVegT expression. Our results highlight the essential role of zVegT in organization of paraxial mesoderm, and reveal that zVegT is regulated by a coherent feedforward loop of Nodal signaling via Eomes.

This study is aimed to examine the association between macronutrient intake and lung function in healthy adults (n = 5880) using the Ansan-Ansung cohort study. To identify the index of lung function, we used the percentage difference of predicted Forced Expiratory Volume (%FEV1_diff) between baseline and follow-up. Based on the median %FEV1_diff, subjects were classified by two groups as “decreased vs. unchanged/improved”. The dietary macronutrients were estimated and validated using the food-frequency questionnaire. Multiple logistic regression models were used to evaluate the association after adjusting for confounders. Advanced analysis examined the association after stratifying by age and obesity. The average of %FEV1 is 114.1 and 112.5 at baseline and follow-up, respectively. The positive association of protein and fiber intake with lung function was observed in men. Low fat and high carbohydrate intake decreased the lung function in women only. After stratification by age, the association of protein, fat, and carbohydrate intake with lung function was observed in young men and old women only. Otherwise, the association of protein and fiber with lung function was influenced by abdominal obesity. In conclusion, the lung function was positively associated with high protein and fat intake, but was negatively associated with high carbohydrate intake, which could be influenced by age and obesity.

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