TRNA hydroxylation is an epitranscriptomic modulator of metabolic states affecting Pseudomonas aeruginosa pathogenicity
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PROVIDER: PRJEB83028 | ENA |
REPOSITORIES: ENA
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Project description:Post-transcriptional modification of tRNAs represents an essential layer of translational regulation critical for bacterial adaptation to environmental changes. Increasing evidence links the tRNA epitranscriptome to pivotal roles in the regulation of gene expression and various cellular processes, including stress responses and the establishment of virulence phenotypes. In this study, we used mass-spectrometry and nanopore sequencing to systematically identify and quantify sites of TrhPO-dependent tRNA hydroxylation in total and purified tRNAs in the opportunistic human pathogen Pseudomonas aeruginosa. Furthermore, transcriptomic, ribosome profiling and proteomic data were integrated to demonstrate the post-transcriptional consequences of the absence of xo5U modifications at wobble positions in selected tRNAs. We show that changes in metabolic fluxes drive the impaired ability to infect host cells and strongly attenuated virulence in the Galleria mellonella model. In the absence of TrhPO-mediated tRNA modification, chorismate, the precursor for the biosynthesis of xo5U-modifications, is funneled into alternative pathways including the production of aromatic amino acids and phenazines. Our findings that metabolic rerouting rather than changes in proteome profiles attenuates P. aeruginosa virulence highlights the multifunctional roles of tRNA-modifying enzymes and suggests an underexplored role for these enzymes in monitoring and modulating metabolic fitness. These insights open new avenues for combatting the pathogenicity of this challenging opportunistic pathogen.
2025-07-30 | GSE283553 | GEO
Project description:tRNA hydroxylation is an epitranscriptomic modulator of metabolic states affecting Pseudomonas aeruginosa pathogenicity
| PRJNA1194520 | ENA
Project description:Post-transcriptional modification of tRNAs represents an essential layer of translational regulation critical for bacterial adaptation to environmental changes. Increasing evidence links the tRNA epitranscriptome to pivotal roles in the regulation of gene expression and various cellular processes, including stress responses and the establishment of virulence phenotypes. In this study, we used mass-spectrometry and nanopore sequencing to systematically identify and quantify sites of TrhPO-dependent tRNA hydroxylation in total and purified tRNAs in the opportunistic human pathogen Pseudomonas aeruginosa. Furthermore, transcriptomic, ribosome profiling and proteomic data were integrated to demonstrate the post-transcriptional consequences of the absence of xo5U modifications at wobble positions in selected tRNAs. We show that changes in metabolic fluxes drive the impaired ability to infect host cells and strongly attenuated virulence in the Galleria mellonella model. In the absence of TrhPO-mediated tRNA modification, chorismate, the precursor for the biosynthesis of xo5U-modifications, is funneled into alternative pathways including the production of aromatic amino acids and phenazines. Our findings that metabolic rerouting rather than changes in proteome profiles attenuates P. aeruginosa virulence highlights the multifunctional roles of tRNA-modifying enzymes and suggests an underexplored role for these enzymes in monitoring and modulating metabolic fitness. These insights open new avenues for combatting the pathogenicity of this challenging opportunistic pathogen.
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Project description:Increasing evidence implicates critical roles of various epitranscriptomic RNA modifications in different biological processes. Methyltransferase METTL8 installs 3-methylcytosine modification of mitochondrial tRNAs in vitro, however, its role in intact biological systems is completely unknown. Here we show that Mettl8 is localized in the mitochondria and installs m3C in mitochondrial tRNASer(UCN)/Thr in mouse embryonic cortical neural stem cells. At molecular and cellular levels, Mettl8 deletion in cortical neural stem cells leads to reduced mitochondrial protein translation and attenuated respiration activity. At the functional level, conditional Mettl8 deletion in mice results in impaired embryonic cortical neural stem cell maintenance in vivo, which can be rescued by pharmacologically enhancing mitochondrial functions. Similarly, METTL8 regulates mitochondrial protein expression and neural stem cell maintenance in human forebrain cortical organoids. Together, our study reveals a conserved epitranscriptomic mechanism of Mettl8 and mitochondrial tRNA m3C modification in maintaining embryonic cortical neural stem cells in mice and humans.
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Project description:This SuperSeries is composed of the following subset Series: GSE32362: Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster (Illumina HumanMethylation450 BeadChip) GSE33129: Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster (Illumina HiSeq2000 sequencing) Refer to individual Series
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2022-08-27 | PXD030726 | Pride
Project description:Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of cancer; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5’tRNA fragments. 5′ tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy, leading to decreased tumour progression. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translational control and tumour biology.
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Project description:Cells respond to environmental stress by regulating gene expression at the level of both transcription and translation. The ~50 modified ribonucleotides of the human epitranscriptome contribute to the latter, with mounting evidence that dynamic regulation of tRNA wobble modifications leads to selective translation of stress response proteins from codon-biased genes. Here we show that the response of human HepG2 cells to arsenite exposure is regulated by the availability of queuine, a micronutrient and essential precursor to the wobble modification queuosine (Q) on tRNAs reading GUN codons. Among oxidizing and alkylating agents at equitoxic concentrations, arsenite exposure caused an oxidant-specific increase in Q that correlated with up-regulation of proteins from codon-biased genes involved in energy metabolism. Limiting queuine increased arsenite-induced cell death, altered translation, increased reactive oxygen species levels, and caused mitochondrial dysfunction. In addition to revealing a new epitranscriptomic facet of arsenite toxicity and response, our results highlight the mechanistic links between environmental exposures, stress tolerance, and micronutrients.
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