Disease-associated mutations in a bifunctional aminoacyl-tRNA synthetase gene elicit the integrated stress response

Jin, Danni; Wek, Sheree A.; Kudlapur, Nathan T.; Cantara, William A.; Bakhtina, Marina; Wek, Ronald C.; Musier‐Forsyth, Karin

doi:10.1016/j.jbc.2021.101203

Cited by 16 publications

(21 citation statements)

References 65 publications

(79 reference statements)

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“…Results from our biochemical studies also point to increased ER stress as indicated by enhanced phosphorylation of eIF2α and increased IRE1α expression. In support of our biochemical data, proteomics analysis revealed the upregulation of proteins involved in the UPR as well as tRNA charging, which is linked to the ISR 41 . Together, these findings are consistent with more rampant defects in N-glycosylation due to limited UDP-GlcNAc in the absence of GFAT1, leading to ER stress 50,51 .…”

Section: Discussionsupporting

confidence: 82%

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Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis

Werlen

Tottone

et al. 2022

Nat Commun

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T cell development requires the coordinated rearrangement of T cell receptor (TCR) gene segments and the expression of either αβ or γδ TCR. However, whether and how de novo synthesis of nutrients contributes to thymocyte commitment to either lineage remains unclear. Here, we find that T cell-specific deficiency in glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1), the rate-limiting enzyme of the de novo hexosamine biosynthesis pathway (dn-HBP), attenuates hexosamine levels, blunts N-glycosylation of TCRβ chains, reduces surface expression of key developmental receptors, thus impairing αβ-T cell ontogeny. GFAT1 deficiency triggers defects in N-glycans, increases the unfolded protein response, and elevates γδ-T cell numbers despite reducing γδ-TCR diversity. Enhancing TCR expression or PI3K/Akt signaling does not reverse developmental defects. Instead, dietary supplementation with the salvage metabolite, glucosamine, and an α-ketoglutarate analogue partially restores αβ-T cell development in GFAT1T-/- mice, while fully rescuing it in ex vivo fetal thymic organ cultures. Thus, dn-HBP fulfils, while salvage nutrients partially satisfy, the elevated demand for hexosamines during early T cell development.

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Section: Discussionsupporting

confidence: 82%

“…3h). Consistent with ISR 41 , GFAT1deficient thymocytes also had enhanced expression of proteins involved in tRNA charging (Fig. 3g).…”

Section: Defective Hexosamine and Nucleotide Biosynthesis Glycosylati...supporting

confidence: 66%

Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis

Werlen

Tottone

et al. 2022

Nat Commun

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“…Plants can respond to abiotic stress by inhibiting protein biosynthesis and increasing levels of molecular chaperones that control protein folding and processing. In protein biosynthesis, the aminoacyl-tRNA synthetases (aaRSs) are essential enzyme-linking amino acids to tRNAs, which provide the building blocks for ribosomal protein synthesis [ 69 ]. It is well documented that aaRSs participate in cellular stress responses in bacteria.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis Revealed Different Molecular Mechanisms of Response to PEG Stress in Drought-Sensitive and Drought-Resistant Sorghums

Yan-ni

Tan

Wang

et al. 2022

IJMS

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Drought is the major limiting factor that directly or indirectly inhibits the growth and reduces the productivity of sorghum (Sorghum bicolor (L.) Moench). As the main vegetative organ of sorghum, the response mechanism of the leaf to drought stress at the proteomic level has not been clarified. In the present study, nano-scale liquid chromatography mass spectrometry (nano-LC-MS/MS) technology was used to compare the changes in the protein expression profile of the leaves of drought-sensitive (S4 and S4-1) and drought-resistant (T33 and T14) sorghum varieties at the seedling stage under 25% PEG-6000 treatment for 24 h. A total of 3927 proteins were accurately quantitated and 46, 36, 35, and 102 differentially abundant proteins (DAPs) were obtained in the S4, S4-1, T14, and T33 varieties, respectively. Four proteins were randomly selected for parallel reaction monitoring (PRM) assays, and the results verified the reliability of the mass spectrometry (MS) results. The response mechanism of the drought-sensitive sorghum leaves to drought was attributed to the upregulation of proteins involved in the tyrosine metabolism pathway with defense functions. Drought-resistant sorghum leaves respond to drought by promoting the TCA cycle, enhancing sphingolipid biosynthesis, interfering with triterpenoid metabolite synthesis, and influencing aminoacyl-tRNA biosynthesis. The 17 screened important candidate proteins related to drought stress were verified by quantitative real-time PCR (qRT-PCR), the results of which were consistent with the results of the proteomic analysis. This study lays the foundation for revealing the drought-resistance mechanism of sorghum at the protein level. These findings will help us cultivate and improve new drought-resistant sorghum varieties.

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“…The majority of genes encoding aaRSs follow the naming convention described above, but there are a few exceptions. EPRS1 encodes a bifunctional glutamyl-prolyl-tRNA synthetase that has the capacity to charge tRNA molecules with either glutamic acid or proline in the cytoplasm ( Cerini et al, 1991 ; Jin et al, 2021 ). The mitochondrial glutaminyl-tRNA synthetase is not encoded for by a separate gene in mammalian species, and it has instead been proposed that an indirect pathway allows for the synthesis of GlnRS in mammalian mitochondria ( Nagao et al, 2009 ).…”

Section: Aars Nomenclature and The Exceptionsmentioning

confidence: 99%

Aminoacyl-tRNA synthetases in human health and disease

Turvey

Horváth²,

Cavalcanti³

2022

Front. Physiol.

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The Aminoacyl-tRNA Synthetases (aaRSs) are an evolutionarily ancient family of enzymes that catalyze the esterification reaction linking a transfer RNA (tRNA) with its cognate amino acid matching the anticodon triplet of the tRNA. Proper functioning of the aaRSs to create aminoacylated (or “charged”) tRNAs is required for efficient and accurate protein synthesis. Beyond their basic canonical function in protein biosynthesis, aaRSs have a surprisingly diverse array of non-canonical functions that are actively being defined. The human genome contains 37 genes that encode unique aaRS proteins. To date, 56 human genetic diseases caused by damaging variants in aaRS genes have been described: 46 are autosomal recessive biallelic disorders and 10 are autosomal dominant monoallelic disorders. Our appreciation of human diseases caused by damaging genetic variants in the aaRSs has been greatly accelerated by the advent of next-generation sequencing, with 89% of these gene discoveries made since 2010. In addition to these genetic disorders of the aaRSs, anti-synthetase syndrome (ASSD) is a rare autoimmune inflammatory myopathy that involves the production of autoantibodies that disrupt aaRS proteins. This review provides an overview of the basic biology of aaRS proteins and describes the rapidly growing list of human diseases known to be caused by genetic variants or autoimmune targeting that affect both the canonical and non-canonical functions of these essential proteins.

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Disease-associated mutations in a bifunctional aminoacyl-tRNA synthetase gene elicit the integrated stress response

Cited by 16 publications

References 65 publications

Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis

Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis

Proteomic Analysis Revealed Different Molecular Mechanisms of Response to PEG Stress in Drought-Sensitive and Drought-Resistant Sorghums

Aminoacyl-tRNA synthetases in human health and disease

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