Queuosine Modification of tRNA-Tyrosine Enhances Growth of Vibrio cholerae with Aminoglycosides by Modulating Translational Efficiency

Konsep Inti

Queuosine (Q) modification of tRNA-Tyrosine by the Tgt enzyme modulates the efficiency of tyrosine codon decoding, leading to translational reprogramming that enhances Vibrio cholerae's growth and tolerance in the presence of sub-lethal aminoglycoside concentrations.

Abstrak

The study investigates how the queuosine (Q) modification of tRNA-Tyrosine by the Tgt enzyme impacts Vibrio cholerae's response to aminoglycoside antibiotics. Key findings:

Deletion of the tgt gene in V. cholerae (Δtgt) leads to decreased growth and tolerance in the presence of sub-lethal concentrations of the aminoglycoside tobramycin (TOB), but not other antibiotics like ciprofloxacin or carbenicillin.

The growth defect of Δtgt is not due to increased antibiotic uptake or changes in proton-motive force. Overexpression of tRNA-Tyr with the native GUA anticodon, but not a synthetic AUA anticodon, restores the growth defect in TOB.

Using molecular reporters, proteomics, and RNA-seq, the authors show that the Q modification impacts the efficiency of decoding at tyrosine TAT and TAC codons. The anti-SoxR factor RsxA, which has a codon bias towards TAT, is more efficiently translated in the absence of tgt. This leads to decreased expression of genes in the SoxR oxidative stress regulon.

Bioinformatic analysis identified other candidate genes with TAT codon bias, including DNA repair factors, that may be subject to translational regulation by the Q modification in response to antibiotic stress.

The authors propose that regulation of Q modification in response to environmental cues, such as sub-lethal antibiotic levels, leads to translational reprogramming of genes with biased tyrosine codon usage, allowing the bacteria to better adapt to the stress.

Statistik

The Δtgt strain shows decreased survival compared to WT after treatment with lethal concentrations of tobramycin (TOB) for 15 minutes to 4 hours, but not with ciprofloxacin (CIP) or carbenicillin (CRB).
The Δtgt strain does not show differences in proton-motive force or neomycin uptake compared to WT.

Kutipan

"Queuosine (Q) modification of tRNA-Tyrosine by the Tgt enzyme modulates the efficiency of tyrosine codon decoding, leading to translational reprogramming that enhances Vibrio cholerae's growth and tolerance in the presence of sub-lethal aminoglycoside concentrations."
"We propose that regulation of Q modification in response to environmental cues, such as sub-lethal antibiotic levels, leads to translational reprogramming of genes with biased tyrosine codon usage, allowing the bacteria to better adapt to the stress."

Wawasan Utama Disaring Dari

Aminoglycoside tolerance in Vibrio cholerae engages translational reprogramming associated to queuosine tRNA modification

by Fruchard,L.,... pada www.biorxiv.org 09-26-2022

https://www.biorxiv.org/content/10.1101/2022.09.26.509455v3

Pertanyaan yang Lebih Dalam

How might the regulation of queuosine modification in response to other environmental stresses, beyond antibiotics, impact bacterial physiology and adaptation?

The regulation of queuosine modification in response to various environmental stresses, not limited to antibiotics, can have significant implications for bacterial physiology and adaptation. Queuosine modification plays a crucial role in modulating translational efficiency and accuracy, impacting the decoding of specific codons. In response to different environmental stresses, the levels of queuosine modification can be dynamically regulated to fine-tune the translation of specific genes. This regulation can lead to translational reprogramming, where certain genes with biased codon usage are preferentially translated under stress conditions.
For example, in the presence of oxidative stress, the absence of queuosine modification may result in altered decoding efficiency of specific codons, leading to changes in the expression of genes involved in oxidative stress response pathways. This can affect the overall stress tolerance and adaptation of bacteria to oxidative conditions. By modulating queuosine levels in response to diverse environmental stresses, bacteria can adjust their translational machinery to optimize the expression of stress-responsive genes, thereby enhancing their survival and adaptation capabilities.

What are the potential mechanisms by which the absence of queuosine modification could lead to increased sensitivity to oxidative stress in Vibrio cholerae?

The absence of queuosine modification in Vibrio cholerae, as seen in the Δtgt mutant, can lead to increased sensitivity to oxidative stress through several potential mechanisms:

Impact on Codon Decoding: Queuosine modification influences the efficiency of decoding specific codons, such as tyrosine TAC and TAT codons. In the absence of queuosine modification, altered decoding at these codons may affect the translation of genes involved in oxidative stress response pathways.

Regulation of Stress Response Genes: Queuosine modification can modulate the translation of stress response genes, including those involved in oxidative stress defense mechanisms. The absence of queuosine modification may disrupt the optimal translation of these genes, leading to decreased expression of proteins essential for combating oxidative stress.

Disruption of Protein Homeostasis: Queuosine modification is known to impact protein synthesis fidelity and accuracy. In the absence of queuosine modification, mistranslation events or errors in protein synthesis may occur, potentially affecting the functionality of proteins involved in oxidative stress response pathways.

Interplay with Other Stress Response Pathways: Queuosine modification may interact with other stress response pathways in the cell. The absence of queuosine modification could disrupt the crosstalk between different stress response mechanisms, leading to a compromised ability to cope with oxidative stress.

Overall, the absence of queuosine modification in Vibrio cholerae can disrupt translational processes, gene expression patterns, and stress response mechanisms, ultimately contributing to increased sensitivity to oxidative stress.

Given the links between tRNA modifications and human diseases, could modulating queuosine levels be a potential therapeutic strategy for treating bacterial infections or other diseases?

Modulating queuosine levels as a therapeutic strategy for treating bacterial infections or other diseases holds promise due to the critical role of tRNA modifications in gene expression and cellular functions. Here are some considerations regarding the potential therapeutic implications of modulating queuosine levels:

Targeting Bacterial Infections: By manipulating queuosine levels in bacterial pathogens, it may be possible to disrupt essential cellular processes, such as protein synthesis, and inhibit bacterial growth. This approach could lead to the development of novel antibacterial strategies that target the translational machinery of pathogens.

Enhancing Antibiotic Efficacy: Modulating queuosine levels in bacteria could potentially enhance the efficacy of existing antibiotics, especially those that target protein synthesis. By sensitizing bacteria to antibiotics through queuosine modulation, it may be possible to overcome antibiotic resistance mechanisms and improve treatment outcomes.

Therapeutic Applications in Human Diseases: Given the emerging links between tRNA modifications and human diseases, including cancer and neurodegenerative disorders, modulating queuosine levels could have therapeutic implications beyond bacterial infections. Targeting queuosine modification pathways in specific disease contexts may offer new avenues for therapeutic intervention.

Precision Medicine Approaches: Understanding the role of queuosine modification in disease pathogenesis could pave the way for personalized medicine approaches that target tRNA modifications based on individual genetic and disease profiles. This precision medicine strategy could lead to more effective and tailored treatments for a range of diseases.

In conclusion, modulating queuosine levels represents a promising therapeutic strategy for addressing bacterial infections and potentially other diseases by targeting key processes involved in gene expression and cellular function. Further research into the specific mechanisms and effects of queuosine modulation is essential to harness its therapeutic potential effectively.