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Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease.

ABSTRACT: Modified uridine containing taurine, 5-taurinomethyluridine (?m5U), is found at the anticodon first position of mitochondrial (mt-)transfer RNAs (tRNAs). Previously, we reported that ?m5U is absent in mt-tRNAs with pathogenic mutations associated with mitochondrial diseases. However, biogenesis and physiological role of ?m5U remained elusive. Here, we elucidated ?m5U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for ?m5U formation catalyzed by MTO1 and GTPBP3. GTPBP3-knockout cells exhibited respiratory defects and reduced mitochondrial translation. Very little ?m5U34 was detected in patient's cells with the GTPBP3 mutation, demonstrating that lack of ?m5U results in pathological consequences. Taurine starvation resulted in downregulation of ?m5U frequency in cultured cells and animal tissues (cat liver and flatfish). Strikingly, 5-carboxymethylaminomethyluridine (cmnm5U), in which the taurine moiety of ?m5U is replaced with glycine, was detected in mt-tRNAs from taurine-depleted cells. These results indicate that tRNA modifications are dynamically regulated via sensing of intracellular metabolites under physiological condition.

SUBMITTER: Asano K

PROVIDER: S-EPMC5829720 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease.

Asano Kana K Suzuki Takeo T Saito Ayaka A Wei Fan-Yan FY Ikeuchi Yoshiho Y Numata Tomoyuki T Tanaka Ryou R Yamane Yoshihisa Y Yamamoto Takeshi T Goto Takanobu T Kishita Yoshihito Y Murayama Kei K Ohtake Akira A Okazaki Yasushi Y Tomizawa Kazuhito K Sakaguchi Yuriko Y Suzuki Tsutomu T

Nucleic acids research 20180201 4

Modified uridine containing taurine, 5-taurinomethyluridine (τm5U), is found at the anticodon first position of mitochondrial (mt-)transfer RNAs (tRNAs). Previously, we reported that τm5U is absent in mt-tRNAs with pathogenic mutations associated with mitochondrial diseases. However, biogenesis and physiological role of τm5U remained elusive. Here, we elucidated τm5U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for τm5U formation catalyzed by ...[more]

PMID: 29390138

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Project description:Backgrounds and aimsTransfer RNA (tRNA) is the most extensively modified RNA in cells. Queuosine modification is a fundamental process for ensuring the fidelity and efficiency of translation from RNA to protein. In eukaryotes, Queuosine tRNA (Q-tRNA) modification relies on the intestinal microbial product queuine. However, the roles and potential mechanisms of Q-containing tRNA (Q-tRNA) modifications in inflammatory bowel disease (IBD) are unknown.MethodsWe explored the Q-tRNA modifications and expression of QTRT1 (queuine tRNA-ribosyltransferase 1) in patients with IBD by investigating human biopsies and reanalyzing datasets. We used colitis models, QTRT1 knockout mice, organoids, and cultured cells to investigate the molecular mechanisms of Q-tRNA modifications in intestinal inflammation.ResultsQTRT1 expression was significantly downregulated in ulcerative colitis and Crohn's disease patients. The 4 Q-tRNA-related tRNA synthetases (asparaginyl-, aspartyl-, histidyl-, and tyrosyl-tRNA synthetase) were decreased in IBD patients. This reduction was further confirmed in a dextran sulfate sodium-induced colitis model and interleukin-10-deficient mice. Reduced QTRT1 was significantly correlated with cell proliferation and intestinal junctions, including downregulation of β-catenin and claudin-5 and the upregulation of claudin-2. These alterations were confirmed in vitro by deleting the QTRT1 gene from cells and in vivo using QTRT1 knockout mice. Queuine treatment significantly enhanced cell proliferation and junction activity in cell lines and organoids. Queuine treatment also reduced inflammation in epithelial cells. Moreover, altered QTRT1-related metabolites were found in human IBD.ConclusionstRNA modifications play an unexplored novel role in the pathogenesis of intestinal inflammation by altering epithelial proliferation and junction formation. Further investigation of the role of tRNA modifications will uncover novel molecular mechanisms for the prevention and treatment of IBD.

Project description:BACKGROUND: Mutation(s) in proteins are a natural byproduct of evolution but can also cause serious diseases. Aminoacyl-tRNA synthetases (aaRSs) are indispensable components of all cellular protein translational machineries, and in humans they drive translation in both cytoplasm and mitochondria. Mutations in aaRSs have been implicated in a plethora of diseases including neurological conditions, metabolic disorders and cancer. RESULTS: We have developed an algorithmic approach for genome-wide analyses of sequence substitutions that combines evolutionary, structural and functional information. This pipeline enabled us to super-annotate human aaRS mutations and analyze their linkage to health disorders. Our data suggest that in some but not all cases, aaRS mutations occur in functional and structural sectors where they can manifest their pathological effects by altering enzyme activity or causing structural instability. Further, mutations appear in both solvent exposed and buried regions of aaRSs indicating that these alterations could lead to dysfunctional enzymes resulting in abnormal protein translation routines by affecting inter-molecular interactions or by disruption of non-bonded interactions. Overall, the prevalence of mutations is much higher in mitochondrial aaRSs, and the two most often mutated aaRSs are mitochondrial glutamyl-tRNA synthetase and dual localized glycyl-tRNA synthetase. Out of 63 mutations annotated in this work, only 12 (~20%) were observed in regions that could directly affect aminoacylation activity via either binding to ATP/amino-acid, tRNA or by involvement in dimerization. Mutations in structural cores or at potential biomolecular interfaces account for ~55% mutations while remaining mutations (~25%) remain structurally un-annotated. CONCLUSION: This work provides a comprehensive structural framework within which most defective human aaRSs have been structurally analyzed. The methodology described here could be employed to annotate mutations in other protein families in a high-throughput manner.

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Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease.

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Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease.

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