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Biological effect of chronic mistranslation in mammalian cells

ABSTRACT: Analysis of HEK293 cells lines expressing mutant ribosomal protein RPS2 (human A226Y). RPS2 A226Y mutation has been shown to cause misreading and readthrough. Results provide insight into the response to chronic mistranslation in mammalian cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115153 | GEO | 2019/09/24

REPOSITORIES: GEO

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Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis

Project description:Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10-4, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum. This study describes the metabolomic analysis of HEK293 cells lines expressing mutant ribosomal protein RPS2 (human A226Y). RPS2 A226Y mutation has been shown to cause misreading and readthrough. Results provide insight into the response to chronic mistranslation in mammalian cells.

2019-09-17 | MTBLS106 | MetaboLights

Biological effect of chronic mistranslation in mammalian cells

Project description:Biological effect of chronic mistranslation in mammalian cells

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Ribosomal mistranslation activates an age-dependent program of dystrophic muscle wasting

Project description:Random errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades. We investigated the impact of translation errors by studying whether mice carrying the ribosomal ambiguity (ram) mutation Rps2-A226Y, recently shown to increase the inborn error rate of translation, if at all viable, presented any specific, possibly aging-related phenotype. We introduced Rps2-A226Y using a Cre/loxP strategy. Resulting transgenic mice were mosaic, with tissue-dependent expression of Rps2-A226Y in 5-30% of cells. We observed a muscle-related phenotype with reduced grip strength and body weight. Analysis of gene expression in skeletal muscle using RNA-Seq revealed changes characteristic of muscle dystrophy occurring in an age-dependent manner, involving an interplay of PGC1α, FOXO3, mTOR, and glucocorticoids as key signalling pathways for muscle function and mitochondrial biogenesis. Our results highlight the relevance of translation accuracy, and show how disturbances thereof can contribute to age-related pathologies.

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Project description:Mistranslation describes the misincorporation of an amino acid into a nascent polypeptide. Mistranslation has diverse effects on multicellular eukaryotes and is implicated in several human diseases. We introduced a mistranslating serine transfer RNA (tRNA) into Drosophila melanogaster that misincorporates serine at proline codons and found that it affected male and female flies differently. Here, we compare the transcriptomic response of male and female flies to mistranslation to identify cellular pathways that underlie this sex-specific response. Both males and females downregulated genes associated with metabolism in response to proline-to-serine mistranslation. Only males downregulated genes associated with developmental processes and response to negative stimuli such as infection, whereas only females downregulated aerobic respiration and ATP synthesis genes. Both sexes upregulated genes associated with gametogenesis but females upregulated cell cycle and DNA maintenance genes, suggesting that mistranslation may compromise genome integrity in females. This transcriptomic analysis advances our understanding of how males and females respond to mistranslation and has important implications for future studies that examine the influence of mistranslation on disease.

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Evolution of robustness to protein mistranslation by accelerated protein turnover

Project description:To investigate how organisms mitigate the deleterious effects of mistranslation during evolution, a mutant tRNA was expressed in S. cerevisiae. The expression of Candida Ser-tRNACAG from a low copy plasmid in S. cerevisiae promoted mistranslation events by random incorporation of both serine and leucine at CUG codons. As mistranslation causes an overload of the protein quality pathways, it disrupts cellular protein homeostasis leading to a major fall in fitness. Laboratory evolutionary experiments were performed to study whether the fitness cost of mistranslation can be lowered. We also wanted to identify the cost-reduction strategy: reducing the frequencies of errors (mitigation), or increasing tolerance to errors (robustness), either by global or local activities. Gene expression was measured in the ancestor (non-evolved) lineage in two different situations: 1) carrying an empty vector and 2) expressing the mutant Ser-tRNACAG. Gene expression was also measured in three ambiguously evolved lineages (B3, D11, H9) in both situations (carrying an empty vector and expressing the mutant tRNA). Three independent experiments were performed for each lineage. Non-evolved strain with empty vector was used as control sample.

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Transcription profiling of S. cerevisiae in the 3 hours after induction of mRNA mistranslation

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Mistranslation accelerates the adaptation of Candida albicans to Fluconazole

Project description:The leucine CUG codon was reassigned to serine in the fungal pathogen Candida albicans. To clarify the biological role of this tuneable codon ambiguity on drug resistance, we evolved C. albicans strains that were engineered to mistranslate the CUG codon at constitutively elevated levels, in the presence and absence of the antifungal drug fluconazole. Elevated levels of mistranslation resulted in the rapid acquisition of resistance to fluconazole.

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