VapC toxin switches M. smegmatis cells into dormancy through 23S rRNA cleavage

Zamakhaev, Mikhail V.; Grigorov, Artem; Bespyatykh, Julia; Azhikina, Tatyana; Гончаренко, А. В.; Шумков, М. С.

doi:10.1007/s00203-022-03363-1

Cited by 4 publications

(6 citation statements)

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“…The mechanism of action of VapC toxin, at least partially, is realized by the cleavage of 23S rRNA, which can lead to the removal of ribosomes from active protein synthesis, their deposition in a membrane-associated state, and the transition of bacterial cells into dormancy. Thus, VapC, like tetracycline, affects the translation apparatus, stopping its functioning, but ensuring preservation in an inactivated state [11]. This could potentially reduce the effectiveness of antibiotic action due to the partial vanishing of the target and the transition of cells into a dormant state; however, the absence of a positive effect of VapC overexpression on the survival of M. smegmatis (Figure 1b) raised doubt about this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…From this perspective, the absence of a positive effect of VapC overexpression on survival under the action of tetracycline (Figure 1b) can be explained as follows. The artificially elevated concentration of the toxin contributes to slowing down growth and transitioning part of the population into a dormant state [11,12]. When tetracycline is added, these dormant cells become less sensitive to the antibiotic.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study, we demonstrated the 23S rRNA cleavage when VapC was overexpressed in M. smegmatis. Additionally, we observed significant alterations in the components of the protein-synthesis machinery under these conditions [11]. In the current work, we analyzed the substantial modifications in the proteins involved in metabolic processes and stress responses according to the proteomic profiling data obtained earlier in M. smegmatis cultures overexpressing VapC (please refer to the data availability statement to find the deposited data).…”

Section: Vapc Overexpression Leads To Proteomic Changes In Abundance ...mentioning

confidence: 99%

“…Thus, under conditions of MazF expression in cells, there is a decrease in the synthesis of critical components of the DNA replication machinery and an increase in the translation of stress response proteins [9]. The vapBC system of M. smegmatis is involved in the regulation of translation by means of 23S rRNA cleavage [10], which is supposed to cause the deactivation of ribosomes and their deposition in a state associated with the membrane [11], ultimately leading to the transition of mycobacterial cells to a dormant state [12]. The physiological effects of vapBC2 are associated with changes in sensitivity to certain antibiotics and oxidative stress, but the molecular mechanism of action of this TA system has not yet been described [7].…”

Section: Introductionmentioning

confidence: 99%

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The Benefits of Toxicity: M. smegmatis VapBC TA Module Is Induced by Tetracycline Exposure and Promotes Survival

Zamakhaev,

Bespyatykh,

Goncharenko

et al. 2023

Microorganisms

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Toxin–antitoxin (TA) systems are widely present in bacterial genomes. Mycolicibacterium smegmatis, a common model organism for studying Mycobacterium tuberculosis physiology, has eight TA loci, including mazEF and vapBC. This study aims to investigate the physiological significance of these TA systems. Proteomic profiling was conducted on a culture overexpressing the VapC toxin, and the involvement of VapC in M. smegmatis stress responses to heat shock and antibiotic treatment was examined. While deciphering the underlying mechanisms of the altered stress resistance, we assessed the antibiotic susceptibility of vapBC, mazEF, and double vapBC-mazEF deletion mutants. Additionally, the mRNA levels of vapC and mazF were measured following tetracycline supplementation. The results reveal changes in the abundance of metabolic enzymes and stress response proteins associated with VapC overexpression. This activation of the general stress response leads to reduced thermosensitivity in M. smegmatis, but does not affect susceptibility to ciprofloxacin and isoniazid. Under tetracycline treatment, both vapC and mazF expression levels are increased, and the fate of the cell depends on the interaction between the corresponding TA systems.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Vapc Overexpression Leads To Proteomic Changes In Abundance ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Benefits of Toxicity: M. smegmatis VapBC TA Module Is Induced by Tetracycline Exposure and Promotes Survival

Zamakhaev,

Bespyatykh,

Goncharenko

et al. 2023

Microorganisms

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“…5b ). Domain III not only forms interactions with Balon but binds to the tip of the GTPase-activating sarcin–ricin loop, which is a known target for cellular toxins and nucleases 40 . Domain I, containing the nucleotide-binding site, forms previously described interactions with the C-terminal domain of the L7/L12 stalk (consisting of protein bL12) 41 and adopts one of two subtly different conformations in our dataset (Extended Data Fig.…”

Section: Balon and Ef-tu In Ribosome Hibernationmentioning

confidence: 99%

A new family of bacterial ribosome hibernation factors

Helena-Bueno,

Rybak,

Ekemezie

et al. 2024

Nature

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To conserve energy during starvation and stress, many organisms use hibernation factor proteins to inhibit protein synthesis and protect their ribosomes from damage1,2. In bacteria, two families of hibernation factors have been described, but the low conservation of these proteins and the huge diversity of species, habitats and environmental stressors have confounded their discovery3–6. Here, by combining cryogenic electron microscopy, genetics and biochemistry, we identify Balon, a new hibernation factor in the cold-adapted bacterium Psychrobacter urativorans. We show that Balon is a distant homologue of the archaeo-eukaryotic translation factor aeRF1 and is found in 20% of representative bacteria. During cold shock or stationary phase, Balon occupies the ribosomal A site in both vacant and actively translating ribosomes in complex with EF-Tu, highlighting an unexpected role for EF-Tu in the cellular stress response. Unlike typical A-site substrates, Balon binds to ribosomes in an mRNA-independent manner, initiating a new mode of ribosome hibernation that can commence while ribosomes are still engaged in protein synthesis. Our work suggests that Balon–EF-Tu-regulated ribosome hibernation is a ubiquitous bacterial stress-response mechanism, and we demonstrate that putative Balon homologues in Mycobacteria bind to ribosomes in a similar fashion. This finding calls for a revision of the current model of ribosome hibernation inferred from common model organisms and holds numerous implications for how we understand and study ribosome hibernation.

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Bacterial Persister Cells and Development of Antibiotic Resistance in Chronic Infections: An Update

Kunnath,

Suodha Suoodh,

Chellappan

et al. 2024

Br J Biomed Sci

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The global issue of antimicrobial resistance poses significant challenges to public health. The World Health Organization (WHO) has highlighted it as a major global health threat, causing an estimated 700,000 deaths worldwide. Understanding the multifaceted nature of antibiotic resistance is crucial for developing effective strategies. Several physiological and biochemical mechanisms are involved in the development of antibiotic resistance. Bacterial cells may escape the bactericidal actions of the drugs by entering a physiologically dormant state known as bacterial persistence. Recent findings in this field suggest that bacterial persistence can be one of the main sources of chronic infections. The antibiotic tolerance developed by the persister cells could tolerate high levels of antibiotics and may give rise to persister offspring. These persister offspring could be attributed to antibiotic resistance mechanisms, especially in chronic infections. This review attempts to shed light on persister-induced antibiotic resistance and the current therapeutic strategies.

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VapC toxin switches M. smegmatis cells into dormancy through 23S rRNA cleavage

Cited by 4 publications

References 57 publications

The Benefits of Toxicity: M. smegmatis VapBC TA Module Is Induced by Tetracycline Exposure and Promotes Survival

The Benefits of Toxicity: M. smegmatis VapBC TA Module Is Induced by Tetracycline Exposure and Promotes Survival

A new family of bacterial ribosome hibernation factors

Bacterial Persister Cells and Development of Antibiotic Resistance in Chronic Infections: An Update

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