Human diseases linked to cytoplasmic aminoacyl-tRNA synthetases

Jiang, Lei; Jones, Julia; Yang, Xiang-Lei

doi:10.1016/bs.enz.2020.06.009

Cited by 21 publications

(23 citation statements)

References 177 publications

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“…Human ARS bi-allelic mutations have been associated with severe multi-organ diseases, including brain and neurological disorders, hearing and visual loss, and liver and lung diseases (44), but the association of diabetes mellitus and skeletal dysplasia was not reported. The compound heterozygous mutations encoded in the ERS domain of EPRS identified in two patients with diabetes and bone disease, P14R and E205G, were not previously associated with human disease and the consequences of these mutations on ERS catalytic function in vitro or on protein synthesis and homeostasis in vivo was unknown.…”

Section: Discussionmentioning

confidence: 99%

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

Jin

Wek

Kudlapur

et al. 2021

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

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

Jin

Wek

Kudlapur

et al. 2021

Journal of Biological Chemistry

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“…Abnormal expression and mutation of ARSs induce abnormal cellular regulation and protein synthesis. The abnormal function of ARSs is associated with a variety of human diseases, such as autoimmune disorders, metabolic disorders, neuronal diseases, and cancer [14]. Some ARSs are abnormally up-regulated or down-regulated in a variety of tumors [15][16][17][18][19][20][21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Identification of LARS as an essential gene for osteosarcoma proliferation through large-Scale CRISPR-Cas9 screening database and experimental verification

et al. 2022

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Background Osteosarcoma is one of the most malignant tumors, and it occurs mostly in children and adolescents. Currently, surgery and chemotherapy are the main treatments. The recurrence rate is high and the prognosis is often poor. Finding an effective target gene therapy for osteosarcoma may effectively improve its prognosis. Method In this study, genes essential for the survival of osteosarcoma cells were identified by genome-wide screening of CRISPR-Cas9 based on the DepMap database. The expression of these essential genes in osteosarcoma patients’ tissues and normal tissues was identified in the GSE19276 database. Functional pathway enrichment analysis, protein interaction network construction, and LASSO were performed to construct a prognostic risk model based on these essential genes. CCK8 assay was used to detect the effect of essential gene-LARS (Leucyl-TRNA Synthetase 1) on the proliferation of osteosarcoma. Results In this study, 785 genes critical for osteosarcoma cell proliferation were identified from the DepMap. Among these 785 essential genes, 59 DEGs were identified in osteosarcoma tissues. In the functional enrichment analysis, these 59 essential genes were mainly enriched in cell cycle-related signaling pathways. Furthermore, we established a risk score module, including LARS and DNAJC17, screened from these 59 genes, and this module could divide osteosarcoma patients into the low-risk and high-risk groups. In addition, knockdown of LARS expression inhibited the proliferative ability of osteosarcoma cells. A significant correlation was found between LARS expression and Monocytic lineage, T cells, and Fibroblasts. Conclusion In conclusion, LARS was identified as an essential gene for survival in osteosarcoma based on the DepMap database. Knockdown of LARS expression significantly inhibited the proliferation of osteosarcoma cells, suggesting that it is involved in the formation and development of osteosarcoma. The results are useful as a foundation for further studies to elucidate a potential osteosarcoma diagnostic index and therapeutic targets.

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“…However, this small group of patients and the fact that five of these autoantibodies were also found in PC, makes it difficult to draw conclusions regarding their potential association with ASSD. Similarly, anti-TrpRS autoantibodies, although previously detected in patients with autoimmune diseases,[14] have not been suggested as a serological marker for ASSD since the related clinical phenotype was more similar to rheumatoid arthritis than ASSD [16, 48]. Nevertheless, all IIM patients with novel anti-aaRS antibodies presented with muscle involvement.…”

Section: Discussionmentioning

confidence: 99%

Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies

Preger

Notarnicola

Hellström

et al. 2022

Preprint

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ObjectivesAutoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory myopathies (IIM). However, up to 40% of IIM patients, even those with clinical manifestations of anti-synthetase syndrome (ASSD), test seronegative to all known myositis-specific autoantibodies (MSAs). We hypothesized the existence of new potential autoantigens among human cytoplasmic aminoacyl tRNA synthetases (aaRS) in patients with IIM.MethodsPlasma samples and clinical data from 217 patients with, 50 patients with ASSD, 165 without, and two with unknown ASSD status were included retrospectively, as well as serum from 156 age/sex-matched population controls. Samples were screened using a multiplex bead array assay for presence of autoantibodies against a panel of 118 recombinant protein variants, representing 33 myositis-related proteins, including all 19 cytoplasmic aaRS.ResultsWe identified reactivity towards 16 aaRS in 72 of the 217 patients. Twelve patients displayed reactivity against nine novel aaRS. The novel autoantibody specificities were detected in four patients previously seronegative for MSAs and in eight with previously detected MSAs. We also confirmed reactivity to four of the most common aaRS (Jo1, PL12, PL7, and EJ (n=45)) and identified patients positive for anti-Zo, -KS, and -HA (n=10) that were not previously tested. A low frequency of anti-aaRS autoantibodies was detected in controls.ConclusionOur results suggest that most, if not all, cytoplasmic aaRS may become autoantigenic. Autoantibodies against new aaRS may be found in plasma of patients previously classified as seronegative with potential high clinical relevance.

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Human diseases linked to cytoplasmic aminoacyl-tRNA synthetases

Cited by 21 publications

References 177 publications

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

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

Identification of LARS as an essential gene for osteosarcoma proliferation through large-Scale CRISPR-Cas9 screening database and experimental verification

Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies

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