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Toxins targeting transfer RNAs: Translation inhibition by bacterial toxin–antitoxin systems

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Prokaryotic toxin–antitoxin (TA) systems are composed of a protein toxin and its cognate antitoxin. These systems are abundant in bacteria and archaea and play an important role in growth regulation. During favorable growth conditions, the antitoxin neutralizes the toxin's activity. However, during conditions of stress or starvation, the antitoxin is inactivated, freeing the toxin to inhibit growth and resulting in dormancy. One mechanism of growth inhibition used by several TA systems results from targeting transfer RNAs (tRNAs), either through preventing aminoacylation, acetylating the primary amino group, or endonucleolytic cleavage. All of these mechanisms inhibit translation and result in growth arrest. Many of these toxins only act on a specific tRNA or a specific subset of tRNAs; however, more work is necessary to understand the specificity determinants of these toxins. For the toxins whose specificity has been characterized, both sequence and structural components of the tRNA appear important for recognition by the toxin. Questions also remain regarding the mechanisms used by dormant bacteria to resume growth after toxin induction. Rescue of stalled ribosomes by transfer‐messenger RNAs, removal of acetylated amino groups from tRNAs, or ligation of cleaved RNA fragments have all been implicated as mechanisms for reversing toxin‐induced dormancy. However, the mechanisms of resuming growth after induction of the majority of tRNA targeting toxins are not yet understood. This article is categorized under: Translation > Translation Regulation RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition
General mechanism of Type II toxin–antitoxin (TA) systems. (a) Depiction of Type II TA operon, where the toxin and antitoxin are co‐transcribed into a single mRNA. During normal growth, the antitoxin binds the toxin and neutralizes its activity. The TA complex represses transcription of the operon. (b) during stress conditions, bacterial proteases degrade the antitoxin, leaving the toxin free to inhibit bacterial growth. Crystal structures of FitAB from Neisseria gonorrhoeae were obtained from the RCSB Protein Data Bank, PDB ID: 2H1C (Mattison, Wilbur, So, & Brennan, ; Rose, Bradley, Valasatava, Duarte, & Prli, ; Rose & Hildebrand, )
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Reversal of toxin‐induced dormancy. RelE and MazF—stalled ribosomes, caused by RelE/MazF cleavage of mRNA in the ribosomal A site, are rescued by tmRNA. TacT—The primary amino group of tRNA is acetylated by TacT, inhibiting translation. Peptidyl‐tRNA hydrolase (Pth) removes the acetylated amino groups, allowing translation to resume
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VapC toxin structure and active site. (a) Crystal structure of VapC from Pyrobaculum aerophilum, including Mg2+ ion (purple) in the active site (Bunker, McKenzie, Baker, & Arcus, ). (b) View of the VapC active site containing a Mg2+ ion. Conserved PIN domain active site amino acid side chains are identified (arrows). Mg2+ ion is coordinated in the active site by the indicated carboxylate side chain oxygen atoms as well as water molecules. Images were produced using the RCSB Protein Data Bank, PDB ID: 2FE1 (Rose et al., ; Rose & Hildebrand, )
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Bacterial persistence. Persisters (red) develop within a replicating bacterial population through either stress‐induced or stochastically generated dormant cells, called persisters. These dormant bacteria are tolerant to antibiotic treatment, as most antibiotics target actively growing cells. Upon completion of antibiotic treatment, the dormant bacteria resume growth and repopulate the niche
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Roles of toxin–antitoxin (TA) systems in bacteria. (a) Postsegregational killing. During cell division, daughter cells that lose a plasmid encoding a TA system will enter a slow growing state or die due to activity of the toxin and loss of antitoxin. (b) Phage abortive infection. Phage infection triggers activation of the TA system, resulting in cell death and preventing phage propagation. However, some phage can mimic the antitoxin, preventing cell death and allowing for phage propagation. (c) Stress survival/antibiotic persistence. During conditions of stress, toxin activity arrests growth leading to a dormant state that can survive the stressful environment. Upon return to favorable conditions, the bacteria resume growth
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Types of toxin–antitoxin (TA) systems. Each of the six types of TA systems are described in the text. Type I systems: The antitoxin (green) is an RNA that binds the toxin mRNA (blue), preventing its translation. Type II systems: The antitoxin is a protein that directly binds its cognate toxin to inhibit its activity. Type III systems: The antitoxin is an RNA that inactivates the toxin protein. Type IV systems: The antitoxin is a protein that protects the cellular target (orange) of the toxin. Type V systems: The antitoxin is a protein that degrades the toxin mRNA. Type VI systems: The antitoxin is a protein that acts as an adaptor between the toxin protein and ClpXP (yellow), which degrades the toxin
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition
Translation > Translation Regulation
RNA in Disease and Development > RNA in Disease

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