Tryptophanyl-tRNA Synthetase as a Potential Therapeutic Target

Ahn, Young Ha; Oh, Se-Chan; Zhou, Shengtao; Kim, Tae-Don

doi:10.3390/ijms22094523

Cited by 15 publications

(14 citation statements)

References 92 publications

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“…Consistent with this notion, we found that MUC1-C is necessary for expression of immunosuppressive indoleamine-2,3-dioxygenase-1 (IDO1), tryptophanyl-tRNA synthetase (WARS, WRS) and PTGES effectors ( Figure 5b ). IRF1 induces (i) IDO1, which reduces tryptophan (Trp) levels in the TME that are necessary for T cell proliferation and function, 49 (ii) WARS that is associated with IDO1 expression and protects cancer cells from Trp depletion, 50 , 51 and (iii) PTGES, which is required for the synthesis of PGE2, an inhibitor of T cell function. 52 Analysis of the TCGA-PRAD and SU2C-CRPC datasets further demonstrated that MUC1-high PCs significantly associate with upregulation of IDO1 ( Figure 5c ; Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

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MUC1-C integrates type II interferon and chromatin remodeling pathways in immunosuppression of prostate cancer

et al. 2022

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The oncogenic MUC1-C protein drives dedifferentiation of castrate resistant prostate cancer (CRPC) cells in association with chromatin remodeling. The present work demonstrates that MUC1-C is necessary for expression of IFNGR1 and activation of the type II interferon-gamma (IFN-γ) pathway. We show that MUC1-C→ARID1A/BAF signaling induces IFNGR1 transcription and that MUC1-C-induced activation of the NuRD complex suppresses FBXW7 in stabilizing the IFNGR1 protein. MUC1-C and NuRD were also necessary for expression of the downstream STAT1 and IRF1 transcription factors. We further demonstrate that MUC1-C and PBRM1/PBAF are necessary for IRF1-induced expression of (i) IDO1, WARS and PTGES, which metabolically suppress the immune tumor microenvironment (TME), and (ii) the ISG15 and SERPINB9 inhibitors of T cell function. Of translational relevance, we show that MUC1 associates with expression of IFNGR1, STAT1 and IRF1, as well as the downstream IDO1, WARS, PTGES, ISG15 and SERPINB9 immunosuppressive effectors in CRPC tumors. Analyses of scRNA-seq data further demonstrate that MUC1 correlates with cancer stem cell (CSC) and IFN gene signatures across CRPC cells. Consistent with these results, MUC1 associates with immune cell-depleted “cold” CRPC TMEs. These findings demonstrate that MUC1-C integrates chronic activation of the type II IFN-γ pathway and induction of chromatin remodeling complexes in linking the CSC state with immune evasion.

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Section: Resultsmentioning

confidence: 99%

“…IRF1 is an essential regulator of downstream effectors, such as IDO1, 49 WARS 50 , 51 and PTGES, 52 that promote immunosuppression of the TME by metabolically inhibiting T cell functions. IRF1 also drives ISG15 56–58 and SERPINB9 59 , 60 that confer resistance of cancer cells to CTL killing.…”

Section: Discussionmentioning

confidence: 99%

MUC1-C integrates type II interferon and chromatin remodeling pathways in immunosuppression of prostate cancer

et al. 2022

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“…The resulting ROS arrests actin dynamics. Sepsis and septic shock are also characterized by increased neutrophil protease levels, i.e., neutrophil elastase, fibrin and matrix metalloproteinases, and MPO, which results in production of WARS [ 54 ]. Aromatic D-tryptophan and D-phenylalanine may elicit a chemotactic response via activation of HCAR3 and fMLP, suggesting their synergistic action on neutrophils [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Tryptophan Metabolism ‘Hub’ Gene Expression Associates with Increased Inflammation and Severe Disease Outcomes in COVID-19 Infection and Inflammatory Bowel Disease

Bustamante

Yau

Boys

et al. 2022

IJMS

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The epithelial barrier’s primary role is to protect against entry of foreign and pathogenic elements. Both COVID-19 and Inflammatory Bowel Disease (IBD) show commonalities in symptoms and treatment with sensitization of the epithelial barrier inviting an immune response. In this study we use a multi-omics strategy to identify a common signature of immune disease that may be able to predict for more severe patient outcomes. Global proteomic approaches were applied to transcriptome and proteome. Further semi- and relative- quantitative targeted mass spectrometry methods were developed to substantiate the proteomic and metabolomics changes in nasal swabs from healthy, COVID-19 (24 h and 3 weeks post infection); serums from Crohn’s disease patients (scored for epithelial leak), terminal ileum tissue biopsies (patient matched inflamed and non-inflamed regions, and controls). We found that the tryptophan/kynurenine metabolism pathway is a ‘hub’ regulator of canonical and non-canonical transcription, macrophage release of cytokines and significant changes in the immune and metabolic status with increasing severity and disease course. Significantly modified pathways include stress response regulator EIF2 signaling (p = 1 × 10−3); energy metabolism, KYNU (p = 4 × 10−4), WARS (p = 1 × 10−7); inflammation, and IDO activity (p = 1 × 10−6). Heightened levels of PARP1, WARS and KYNU are predictive at the acute stage of infection for resilience, while in contrast, levels remained high and are predictive of persistent and more severe outcomes in COVID disease. Generation of a targeted marker profile showed these changes in immune disease underlay resolution of epithelial barrier function and have the potential to define disease trajectory and more severe patient outcomes.

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“…However, its host gene, WARS, encodes the enzyme tryptophanyl-tRNA synthetase, which is known to catalyze the tryptophan-tRNA ligation, which is key for protein synthesis [ 54 ]. WARS has been previously studied for its role in the innate inflammatory response, where it was found to act via Toll-like receptor activation and regulate the immune cell response [ 54 , 55 , 56 ]. In the present study, we showed that circWARS harbored multiple binding sites for key β-cell miRNAs and RBPs, including Ago2.…”

Section: Discussionmentioning

confidence: 99%

Pro-Inflammatory Cytokines Promote the Transcription of Circular RNAs in Human Pancreatic β Cells

Kaur

Frørup

Mirza

et al. 2022

ncRNA

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Circular RNAs (circRNAs) have recently been implicated in impaired β-cell function in diabetes. Using microarray-based profiling of circRNAs in human EndoC-βH1 cells treated with pro-inflammatory cytokines, this study aimed to investigate the expression and possible regulatory roles of circRNAs in human β cells. We identified ~5000 β-cell-expressed circRNAs, of which 84 were differentially expressed (DE) after cytokine exposure. Pathway analysis of the host genes of the DE circRNAs revealed the enrichment of cytokine signaling pathways, indicative of circRNA transcription from inflammatory genes in response to cytokines. Multiple binding sites for β-cell-enriched microRNAs and RNA-binding proteins were observed for the highly upregulated circRNAs, supporting their function as ‘sponges’ or ‘decoys’. We also present evidence for circRNA sequence conservation in multiple species, the presence of cytokine-induced regulatory elements, and putative protein-coding potential for the DE circRNAs. This study highlights the complex regulatory potential of circRNAs, which may play a crucial role during immune-mediated β-cell destruction in type 1 diabetes.

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Tryptophanyl-tRNA Synthetase as a Potential Therapeutic Target

Cited by 15 publications

References 92 publications

MUC1-C integrates type II interferon and chromatin remodeling pathways in immunosuppression of prostate cancer

MUC1-C integrates type II interferon and chromatin remodeling pathways in immunosuppression of prostate cancer

Tryptophan Metabolism ‘Hub’ Gene Expression Associates with Increased Inflammation and Severe Disease Outcomes in COVID-19 Infection and Inflammatory Bowel Disease

Pro-Inflammatory Cytokines Promote the Transcription of Circular RNAs in Human Pancreatic β Cells

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