Isoleucyl-tRNA synthetase 1 novel mutation promotes deposition of pulmonary surfactant through stabilizing Cathepsin Z
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE250412 | GEO | 2025/12/01
REPOSITORIES: GEO
Similar Datasets
Project description:Isoleucyl-tRNA synthetase 1(IARS1) disorder is a recently identified multi-organ disease, only a limited cases have been reported so far; furthermore, the mechanisms underlying IARS1 mutation and the symptoms remain unknown. In this report, we present four families with seven distinct IARS1 variants, associated with growth retardation, fatty liver, mental development disorder, and severe pulmonary alveolar proteinosis. IARS1-Tyr148Cys/Arg444* mice are established and exhibited pulmonary alveolar proteinosis and other multi-organ disorders that closely mimic human phenotype. Analysis of single cell RNA sequencing of peripheral blood mononuclear cells from patients and lung metabolomics of lung in IARS1-Tyr148Cys/Arg444* mice analysis indicated disruption in phagosome, lysosome and fatty acid metabolism, cholesterol metabolism pathways. IARS1 mutations results in accumulation of surfactant in alveolar macrophages and alveoli in compound heterozygous mouse model, while IARS1 deficiency impairs the post-translation of Cathepsin Z(CTSZ) by inhibiting ubiquitin-mediated degradation. CTSZ depleted also shows abnormal cholesterol degradation and deposition of pulmonary surfactant associated proteins and overexpression CTSZ could rescue IARS1 deficiency related alveolar macrophage disfunction in vitro. These finding suggest that biallelic IARS1 deficiency impair alveolar macrophage, partly by impair CTSZ -dependent degeneration; and IARS1 could consider as a candidate gene in inherit pulmonary alveolar proteinosis.
2025-12-01 | GSE250411 | GEO
Project description:Isoleucyl-tRNA synthetase 1(IARS1) disorder is a recently identified multi-organ disease, only a limited cases have been reported so far; furthermore, the mechanisms underlying IARS1 mutation and the symptoms remain unknown. In this report, we present four families with seven distinct IARS1 variants, associated with growth retardation, fatty liver, mental development disorder, and severe pulmonary alveolar proteinosis. IARS1-Tyr148Cys/Arg444* mice are established and exhibited pulmonary alveolar proteinosis and other multi-organ disorders that closely mimic human phenotype. Analysis of single cell RNA sequencing of peripheral blood mononuclear cells from patients and lung metabolomics of lung in IARS1-Tyr148Cys/Arg444* mice analysis indicated disruption in phagosome, lysosome and fatty acid metabolism, cholesterol metabolism pathways. IARS1 mutations results in accumulation of surfactant in alveolar macrophages and alveoli in compound heterozygous mouse model, while IARS1 deficiency impairs the post-translation of Cathepsin Z(CTSZ) by inhibiting ubiquitin-mediated degradation. CTSZ depleted also shows abnormal cholesterol degradation and deposition of pulmonary surfactant associated proteins and overexpression CTSZ could rescue IARS1 deficiency related alveolar macrophage disfunction in vitro. These finding suggest that biallelic IARS1 deficiency impair alveolar macrophage, partly by impair CTSZ -dependent degeneration; and IARS1 could consider as a candidate gene in inherit pulmonary alveolar proteinosis.
2025-12-01 | GSE250270 | GEO
Project description:Isoleucyl-tRNA synthetase 1 novel mutation promotes deposition of pulmonary surfactant through stabilizing Cathepsin Z
| PRJNA1053925 | ENA
Project description:Isoleucyl-tRNA synthetase 1 novel mutation promotes deposition of pulmonary surfactant through stabilizing Cathepsin Z [RNA-seq]
| PRJNA1053276 | ENA
Project description:Isoleucyl-tRNA synthetase 1 novel mutation promotes deposition of pulmonary surfactant through stabilizing Cathepsin Z [scRNA-seq]
| PRJNA1053926 | ENA
Project description:Isoleucyl-tRNA synthetase 2 (IARS2), originally regarded as an enzyme ligating isoleucine to the corresponding tRNA, has been identified as an oncogene recently. However, its function in pancreatic ductal adenocarcinoma (PDAC) remains to be discovered. Here we explored the biological role of IARS2 in PDAC. Up-regulated IARS2 was found in PDAC tissues and cell lines. Kaplan-Meier survival analysis indicated a worse prognosis in patients with high IARS2 expression. CCK-8, EdU, and colony formation assays showed IARS2 overexpression enhanced PDAC proliferation, which was reduced by IARS2 knockdown. Meanwhile, IARS2 down-regulation inhibited PDAC metastasis by impeding epithelial-mesenchymal transition. These results were also supported by subcutaneous xenograft and metastasis assays in vivo. To figure out underlying mechanisms, differential and enrichment analyses were conducted and the WNT signaling pathway was discovered. Our results demonstrated that there was no significant relationship between the WNT signaling pathway key factor CTNNB1 and IARS2 at the transcription level. However, cycloheximide assays showed that IARS2 reduced the β-catenin degradation rate. IARS2 inhibited the phosphorylation of β-catenin at the Ser33/37 site and regulated downstream targets of WNT signaling including c-MYC, c-JUN, and MMP7. The enhancement of proliferation and metastasis caused by IARS2 could be reversed by MSAB, an agent that promotes β-catenin degradation. In summary, IARS2 facilitates PDAC proliferation and metastasis by stabilizing β-catenin, which leads to WNT/β-catenin activation. IARS2 serves as an underlying prognosis marker and a potential therapeutic target for PDAC.
| S-EPMC11907448 | biostudies-literature
Project description:Hyperuricemia, pulmonary hypertension, and renal failure in infancy and alkalosis syndrome (HUPRA syndrome) is an ultrarare mitochondrial disease that is characterized by hyperuricemia, pulmonary hypertension, renal failure, and alkalosis. Seryl-tRNA synthetase 2 (SARS2) gene variants are believed to cause HUPRA syndrome, and these variants result in the loss of function of seryl-tRNA synthetase. Eventually, mutated seryl-tRNA synthetase is unable to catalyze tRNA synthesis and leads to the inhibition of the biosynthesis of mitochondrial proteins. This causes oxidative phosphorylation (OXPHOS) system impairments. To date, five mutation sites in the SARS2 gene have been identified. We used whole-exome sequencing and Sanger sequencing to find and validate a novel compound heterozygous variants of SARS2 [c.1205G>A (p.Arg402His) and c.680G>A (p.Arg227Gln)], and in silico analysis to analyze the structural change of the variants. We found that both variants were not sufficient to cause obvious structural damage but changed the intermolecular bond of the protein, which could be the cause of HUPRA syndrome in this case. We also performed the literature review and found this patient had significant pulmonary hypertension and minor renal dysfunction compared with other reported cases. This study inspired us to recognize HUPRA syndrome and broaden our knowledge of gene variation in PH.
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Project description:mTORC1 is an important regulator of muscle mass but how it is modulated by oxygen and nutrients is not completely understood. We show that loss of the prolyl hydroxylase domain isoform 1 oxygen sensor in mice (PHD1KO) reduces muscle mass. PHD1KO muscles show impaired mTORC1 activation in response to leucine whereas mTORC1 activation by growth factors or eccentric contractions was preserved. The ability of PHD1 to promote mTORC1 activity is independent of its hydroxylation activity but is caused by decreased protein content of the leucyl tRNA synthetase (LRS) leucine sensor. Mechanistically, PHD1 interacts with and stabilizes LRS. This interaction is promoted during oxygen and amino acid depletion and protects LRS from degradation. Finally, elderly subjects have lower PHD1 levels and LRS activity in muscle from aged versus young human subjects. In conclusion, PHD1 ensures an optimal mTORC1 response to leucine after episodes of metabolic scarcity.
| S-EPMC6954236 | biostudies-literature
Project description:Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, among which hydroxyacyl-CoA dehydrogenase mRNA encodes for a key enzyme in fatty acid oxidation. Resistant melanoma cultures rely on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for their survival upon MAPK treatment. Together, our data demonstrate that VARS may represent an attractive therapeutic target for the treatment of therapy-resistant melanoma.
| S-EPMC11252002 | biostudies-literature
Project description:This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes, which has not been depicted by the known neurodegenerative disease. We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia, Parkinsonism, and cognitive function, as well as brain magnetic resonance imaging scans with seven sequences. We searched for co-segregations of abnormal repeat-expansion loci, pathogenic variants in known spinocerebellar ataxia-related genes, and novel rare mutations via whole-genome sequencing and linkage analysis. A rare co-segregating missense mutation in the CARS gene was validated by Sanger sequencing and the aminoacylation activity of mutant CARS was measured by spectrophotometric assay. This pedigree presented novel late-onset core characteristics including cerebellar ataxia, Parkinsonism, and pyramidal signs in all nine affected members. Brain magnetic resonance imaging showed cerebellar/pons atrophy, pontine-midline linear hyperintensity, decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus, and hypo-intensities of the cerebellar dentate nuclei, basal ganglia, mesencephalic red nuclei, and substantia nigra, all of which suggested neurodegeneration. Whole-genome sequencing identified a novel pathogenic heterozygous mutation (E795V) in the CARS gene, meanwhile, exhibited none of the known repeat-expansions or point mutations in pathogenic genes. Remarkably, this CARS mutation causes a 20% decrease in aminoacylation activity to charge tRNACys with L-cysteine in protein synthesis compared with that of the wild type. All family members carrying a heterozygous mutation CARS (E795V) had the same clinical manifestations and neuropathological changes of Parkinsonism and spinocerebellar-ataxia. These findings identify novel pathogenesis of Parkinsonism-spinocerebellar ataxia and provide insights into its genetic architecture.
| S-EPMC11422396 | biostudies-literature