Comprehensive characterization of mRNAs associated with yeast cytosolic aminoacyl-tRNA synthetases

Garin, Shahar; Levi, Ofri; Forrest, Megan E.; Antonellis, Anthony; Arava, Yoav

doi:10.1080/15476286.2021.1935116

Cited by 10 publications

(10 citation statements)

References 46 publications

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“…All these findings pinpointed that EARS2 is very likely to be involved in the process of CoVs infections, and especially serves as a critical factor mediating SARS-CoV2 infection in the host. Of interest, some aaRSs have been revealed to target mRNAs through binding tRNA-like elements, suggesting a mode of mRNA regulation by aaRSs (Levi and Arava, 2019;Garin et al, 2021). In addition, RNA viruses can hijack host cellular machinery by mimicking the tRNA-like structure to trick host aaRSs (Bonilla et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The Landscape of Aminoacyl-tRNA Synthetases Involved in Severe Acute Respiratory Syndrome Coronavirus 2 Infection

et al. 2022

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Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in translation by linking amino acids onto their cognate tRNAs during protein synthesis. During evolution, aaRSs develop numerous non-canonical functions that expand the roles of aaRSs in eukaryotic organisms. Although aaRSs have been implicated in viral infection, the function of aaRSs during infections with coronaviruses (CoVs) remains unclear. Here, we analyzed the data from transcriptomic and proteomic database on human cytoplasmic (cyto) and mitochondrial (mt) aaRSs across infections with three highly pathogenic human CoVs, with a particular focus on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We found an overall downregulation of aaRSs at mRNA levels, while the protein levels of some mt-aaRSs and the phosphorylation of certain aaRSs were increased in response to SARS-CoV-2 infection. Strikingly, interaction network between SARS-CoV-2 and human aaRSs displayed a strong involvement of mt-aaRSs. Further co-immunoprecipitation (co-IP) experiments confirmed the physical interaction between SARS-CoV-2 M protein and TARS2. In addition, we identified the intermediate nodes and potential pathways involved in SARS-CoV-2 infection. This study provides an unbiased, overarching perspective on the correlation between aaRSs and SARS-CoV-2. More importantly, this work identifies TARS2, HARS2, and EARS2 as potential key factors involved in COVID-19.

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Section: Discussionmentioning

confidence: 99%

The Landscape of Aminoacyl-tRNA Synthetases Involved in Severe Acute Respiratory Syndrome Coronavirus 2 Infection

et al. 2022

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“…Although several researches have suggested non-canonical function, such as post-transcriptional regulation of mRNA expression, in some aaRSs [ 55 ]. No evidence for FARS2 function other than mitochondrial translation activity has been shown yet.…”

Section: Discussionmentioning

confidence: 99%

Neuropathy-associated Fars2 deficiency affects neuronal development and potentiates neuronal apoptosis by impairing mitochondrial function

Chen

Liu

et al. 2022

Cell Biosci

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Background Neurodegenerative diseases encompass an extensive and heterogeneous group of nervous system disorders which are characterized by progressive degeneration and death of neurons. Many lines of evidence suggest the participation of mitochondria dysfunction in these diseases. Mitochondrial phenylalanyl-tRNA synthetase, encoded by FARS2, catalyzes the transfer of phenylalanine to its cognate tRNA for protein synthesis. As a member of mt-aaRSs genes, FARS2 missense homozygous mutation c.424G > T (p.D142Y) found in a Chinese consanguineous family first built the relationship between pure hereditary spastic paraplegia (HSP) and FARS2 gene. More FARS2 variations were subsequently found to cause heterogeneous group of neurologic disorders presenting three main phenotypic manifestations: infantile-onset epileptic mitochondrial encephalopathy, later-onset spastic paraplegia and juvenile onset refractory epilepsy. Studies showed that aminoacylation activity is frequently disrupt in cases with FARS2 mutations, indicating a loss-of-function mechanism. However, the underlying pathogenesis of neuropathy-associated Fars2 deficiency is still largely unknown. Results Early gestation lethality of global Fars2 knockout mice was observed prior to neurogenesis. The conditional Fars2 knockout-mouse model delayed lethality to late-gestation, resulting in a thinner cortex and an enlarged ventricle which is consist with the MRI results revealing cortical atrophy and reduced cerebral white matter volume in FARS2-deficient patients. Delayed development of neurite outgrowth followed by neuronal apoptosis was confirmed in Fars2-knockdown mouse primary cultured neurons. Zebrafish, in which fars2 was knocked down, exhibited aberrant motor neuron function including reduced locomotor capacity which well restored the spastic paraplegia phenotype of FARS2-deficient patients. Altered mitochondrial protein synthesis and reduced levels of oxidative phosphorylation complexes were detected in Fars2-deficient samples. And thus, reduced ATP, total NAD levels and mitochondrial membrane potential, together with increased ROS production, revealed mitochondrial dysfunction both in vitro and in vivo. Dctn3 is a potential downstream molecule in responds to Fars2 deficient in neurons, which may provide some evidence for the development of pathogenesis study and therapeutic schedule. Conclusions The Fars2 deficiency genetic models developed in this study cover the typical clinical manifestations in FARS2 patients, and help clarify how neuropathy-associated Fars2 deficiency, by damaging the mitochondrial respiratory chain and impairing mitochondrial function, affects neuronal development and potentiates neuronal cell apoptosis.

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“…Aminoacyl‐tRNA synthases are conserved enzymes with important roles in protein synthesis, coordinating mRNA expression in response to amino acid utilization 38 . Glycine, serine, and threonine metabolism, alanine, aspartate, and glutamate metabolism, phenylalanine metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, and arginine biosynthesis were significantly disrupted in serum and brain, which implied an interference in protein syntheses in the HFrD group.…”

Section: Discussionmentioning

confidence: 99%

Impact of a long‐term high‐fructose diet on systemic metabolic profiles of mice

Wang

Han

et al. 2022

FASEB BioAdvances

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Evidence is mounting that chronic high‐fructose diets (HFrD) can lead to metabolic abnormalities and cause a variety of diseases. However, the underlying mechanism by which long‐term high fructose intake influencing systemic metabolism remains unclarified. This study, therefore, attempted to investigate the impact of a high‐fructose diet on metabolic profile. Four‐week‐old male C57BL/6 mice were fed with 15% fructose solution as their only source of water for 8 weeks. Afterward, gas chromatography–mass spectrometry (GC–MS) was employed to investigate the comprehensive metabolic profile of serum, muscle, liver, heart, white adipose, brain, and kidney tissues, and multivariate analyses including principal component analysis (PCA) and orthogonal partial least squared‐discriminant analysis (OPLS‐DA) were applied to screen for differential metabolite expression between the HFrD and control groups. Furthermore, the MetaboAnalyst 5.0 ( http://www.metaboanalyst.ca ) and Kyoto Encyclopedia of Genes and Genomes database (KEGG; http://www.kegg.jp ) were employed to portray a detailed metabolic network. This study identified 62 metabolites related to HFrD and 10 disturbed metabolic pathways. The results indicated that high fructose intake mainly influenced amino acid metabolism and biosynthesis (glycine, serine, and threonine metabolism; aspartate, and glutamate metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis, and arginine biosynthesis pathways), glutathione metabolism, sphingolipid metabolism, and glyoxylate and dicarboxylate metabolism in serum, whereas these pathways were suppressed in the brain. Starch and sucrose metabolism in muscle was also disrupted. These results elucidate the effects of long‐term high fructose consumption on the metabolic profiles of various tissues and provide new insight for the identification of potential metabolic biomarkers and pathways disrupted by high fructose.

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Comprehensive characterization of mRNAs associated with yeast cytosolic aminoacyl-tRNA synthetases

Cited by 10 publications

References 46 publications

The Landscape of Aminoacyl-tRNA Synthetases Involved in Severe Acute Respiratory Syndrome Coronavirus 2 Infection

The Landscape of Aminoacyl-tRNA Synthetases Involved in Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Neuropathy-associated Fars2 deficiency affects neuronal development and potentiates neuronal apoptosis by impairing mitochondrial function

Impact of a long‐term high‐fructose diet on systemic metabolic profiles of mice

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