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Sub-cellular Biochemistry 2017Toxin-antitoxin systems are widespread in the bacterial kingdom, including in pathogenic species, where they allow rapid adaptation to changing environmental conditions... (Review)
Review
Toxin-antitoxin systems are widespread in the bacterial kingdom, including in pathogenic species, where they allow rapid adaptation to changing environmental conditions through selective inhibition of key cellular processes, such as DNA replication or protein translation. Under normal growth conditions, type II toxins are inhibited through tight protein-protein interaction with a cognate antitoxin protein. This toxin-antitoxin complex associates into a higher-order macromolecular structure, typically heterotetrameric or heterooctameric, exposing two DNA binding domains on the antitoxin that allow auto-regulation of transcription by direct binding to promoter DNA. In this chapter, we review our current understanding of the structural characteristics of type II toxin-antitoxin complexes in bacterial cells, with a special emphasis on the staggering variety of higher-order architecture observed among members of the VapBC family. This structural variety is a result of poor conservation at the primary sequence level and likely to have significant and functional implications on the way toxin-antitoxin expression is regulated.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; DNA-Binding Proteins
PubMed: 28271484
DOI: 10.1007/978-3-319-46503-6_14 -
Current Genetics May 2016Toxin-antitoxin (TA) systems are widely conserved in prokaryotic plasmids and chromosomes and are linked to many roles in cell physiology, including plasmid maintenance,... (Review)
Review
Toxin-antitoxin (TA) systems are widely conserved in prokaryotic plasmids and chromosomes and are linked to many roles in cell physiology, including plasmid maintenance, stress response, persistence and protection from phage infection. A TA system is composed of a stable toxin and a labile antitoxin that inhibits a harmful effect of the cognate toxin. When gene expression from the TA loci is repressed under certain conditions such as nutrient starvation, the toxin is freed from the rapidly degrading antitoxin and obstructs an essential cellular process, such as DNA replication, translation and peptidoglycan synthesis, which subsequently causes growth arrest. TA systems are classified into five types according to the nature and the function of antitoxins, and the activity of toxins is tightly regulated in a variety of ways. This short-review highlights several novel regulatory mechanisms for Escherichia coli toxins that we recently discovered.
Topics: Antitoxins; Bacteriophage T4; DNA Replication; Escherichia coli; Protein Biosynthesis
PubMed: 26780368
DOI: 10.1007/s00294-015-0557-z -
Sheng Wu Gong Cheng Xue Bao = Chinese... Sep 2022Bacteria are often infected by large numbers of phages, and host bacteria have evolved diverse molecular strategies in the race with phages, with abortive infection... (Review)
Review
Bacteria are often infected by large numbers of phages, and host bacteria have evolved diverse molecular strategies in the race with phages, with abortive infection (Abi) being one of them. The toxin-antitoxin system (TA) is expressed in response to bacterial stress, mediating hypometabolism and even dormancy, as well as directly reducing the formation of offspring phages. In addition, some of the toxins' sequences and structures are highly homologous to Cas, and phages even encode antitoxin analogs to block the activity of the corresponding toxins. This suggests that the failure of phage infection due to bacterial death in abortive infections is highly compatible with TA function, whereas TA may be one of the main resistance and defense forces for phage infestation of the host. This review summarized the TA systems involved in phage abortive infections based on classification and function. Moreover, TA systems with abortive functions and future use in antibiotic development and disease treatment were predicted. This will facilitate the understanding of bacterial-phage interactions as well as phage therapy and related synthetic biology research.
Topics: Anti-Bacterial Agents; Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; Bacteriophages; Toxin-Antitoxin Systems
PubMed: 36151800
DOI: 10.13345/j.cjb.220140 -
Cell Reports Dec 2022Temperate phages dynamically switch between lysis and lysogeny in their full life cycle. Some Bacillus-infecting phages utilize a quorum-sensing-like intercellular...
Temperate phages dynamically switch between lysis and lysogeny in their full life cycle. Some Bacillus-infecting phages utilize a quorum-sensing-like intercellular communication system, the "arbitrium," to mediate lysis-lysogeny decisions. However, whether additional factors participate in the arbitrium signaling pathway remains largely elusive. Here, we find that the arbitrium signal induces the expression of a functionally conserved operon downstream of the arbitrium module in SPbeta-like phages. SPbeta yopM and yopR (as well as phi3T phi3T_93 and phi3T_97) in the operon play roles in suppressing phage lytic propagation and promoting lysogeny, respectively. We further focus on phi3T_93 and demonstrate that it directly binds antitoxin MazE in the host MazF/MazE toxin-antitoxin (TA) module and facilitates the activation of MazF's toxicity, which is required for phage suppression. These findings show events regulated by the arbitrium system and shed light on how the interplay between phages and the host TA module affects phage-host co-survival.
Topics: Antitoxins; Bacteriophages
PubMed: 36476854
DOI: 10.1016/j.celrep.2022.111752 -
Microbiology (Reading, England) Jul 2017Most bacterial genomes have multiple type II toxin-antitoxin systems (TAs) that encode two proteins which are referred to as a toxin and an antitoxin. Toxins inhibit a... (Review)
Review
Most bacterial genomes have multiple type II toxin-antitoxin systems (TAs) that encode two proteins which are referred to as a toxin and an antitoxin. Toxins inhibit a cellular process, while the interaction of the antitoxin with the toxin attenuates the toxin's activity. Endoribonuclease-encoding TAs cleave RNA in a sequence-dependent fashion, resulting in translational inhibition. To account for their prevalence and retention by bacterial genomes, TAs are credited with clinically significant phenomena, such as bacterial programmed cell death, persistence, biofilms and anti-addiction to plasmids. However, the programmed cell death and persistence hypotheses have been challenged because of conceptual, methodological and/or strain issues. In an alternative view, chromosomal TAs seem to be retained by virtue of addiction at two levels: via a poison-antidote combination (TA proteins) and via transcriptional reprogramming of the downstream core gene (due to integration). Any perturbation in the chromosomal TA operons could cause fitness loss due to polar effects on the downstream genes and hence be detrimental under natural conditions. The endoribonucleases encoding chromosomal TAs are most likely selfish DNA as they are retained by bacterial genomes, even though TAs do not confer a direct advantage via the TA proteins. TAs are likely used by various replicons as 'genetic arms' that allow the maintenance of themselves and associated genetic elements. TAs seem to be the 'selfish arms' that make the best use of the 'arms race' between bacterial genomes and plasmids.
Topics: Antitoxins; Bacteria; Bacterial Toxins; Endoribonucleases; Toxin-Antitoxin Systems
PubMed: 28691660
DOI: 10.1099/mic.0.000487 -
Molecular Cell Jun 2018Bacterial toxin-antitoxin (TA) modules are abundant genetic elements that encode a toxin protein capable of inhibiting cell growth and an antitoxin that counteracts the... (Review)
Review
Bacterial toxin-antitoxin (TA) modules are abundant genetic elements that encode a toxin protein capable of inhibiting cell growth and an antitoxin that counteracts the toxin. The majority of toxins are enzymes that interfere with translation or DNA replication, but a wide variety of molecular activities and cellular targets have been described. Antitoxins are proteins or RNAs that often control their cognate toxins through direct interactions and, in conjunction with other signaling elements, through transcriptional and translational regulation of TA module expression. Three major biological functions of TA modules have been discovered, post-segregational killing ("plasmid addiction"), abortive infection (bacteriophage immunity through altruistic suicide), and persister formation (antibiotic tolerance through dormancy). In this review, we summarize the current state of the field and highlight how multiple levels of regulation shape the conditions of toxin activation to achieve the different biological functions of TA modules.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; Drug Resistance, Bacterial; Evolution, Molecular; Gene Expression Regulation, Bacterial; Immunity, Innate; Microbial Viability; Models, Molecular; Nucleic Acid Conformation; Protein Conformation; RNA Processing, Post-Transcriptional; RNA, Bacterial; Structure-Activity Relationship; Transcription, Genetic
PubMed: 29398446
DOI: 10.1016/j.molcel.2018.01.003 -
Toxins Jan 2014Genes for toxin-antitoxin (TA) complexes are widely disseminated in bacteria, including in pathogenic and antibiotic resistant species. The toxins are liberated from... (Review)
Review
Genes for toxin-antitoxin (TA) complexes are widely disseminated in bacteria, including in pathogenic and antibiotic resistant species. The toxins are liberated from association with the cognate antitoxins by certain physiological triggers to impair vital cellular functions. TAs also are implicated in antibiotic persistence, biofilm formation, and bacteriophage resistance. Among the ever increasing number of TA modules that have been identified, the most numerous are complexes in which both toxin and antitoxin are proteins. Transcriptional autoregulation of the operons encoding these complexes is key to ensuring balanced TA production and to prevent inadvertent toxin release. Control typically is exerted by binding of the antitoxin to regulatory sequences upstream of the operons. The toxin protein commonly works as a transcriptional corepressor that remodels and stabilizes the antitoxin. However, there are notable exceptions to this paradigm. Moreover, it is becoming clear that TA complexes often form one strand in an interconnected web of stress responses suggesting that their transcriptional regulation may prove to be more intricate than currently understood. Furthermore, interference with TA gene transcriptional autoregulation holds considerable promise as a novel antibacterial strategy: artificial release of the toxin factor using designer drugs is a potential approach to induce bacterial suicide from within.
Topics: Antitoxins; Bacterial Proteins; DNA Gyrase; DNA, Bacterial; Epigenetic Repression; Escherichia coli; Toxins, Biological; Transcriptional Activation
PubMed: 24434949
DOI: 10.3390/toxins6010337 -
Pathogens and Disease Apr 2014One of the most pertinent recent outcomes of molecular microbiology efforts to understand bacterial behavior is the discovery of a wide range of toxin-antitoxin (TA)... (Review)
Review
One of the most pertinent recent outcomes of molecular microbiology efforts to understand bacterial behavior is the discovery of a wide range of toxin-antitoxin (TA) systems that are tightly controlling bacterial persistence. While TA systems were originally linked to control over the genetic material, for example plasmid maintenance, it is now clear that they are involved in essential cellular processes like replication, gene expression, and cell wall synthesis. Toxin activity is induced stochastically or after environmental stimuli, resulting in silencing of the above-mentioned biological processes and entry in a dormant state. In this minireview, we highlight the recent developments in research on these intriguing systems with a focus on their role in biofilms and in bacterial virulence. We discuss their potential as targets in antimicrobial drug discovery.
Topics: Anti-Infective Agents; Antitoxins; Biofilms; Drug Discovery; Humans; Toxins, Biological; Virulence
PubMed: 24478112
DOI: 10.1111/2049-632X.12145 -
Plasmid Jul 2013Toxin-antitoxin systems are widely distributed among many bacterial species, including human pathogens. Typically, these systems consist of two genes in an operon which... (Review)
Review
Toxin-antitoxin systems are widely distributed among many bacterial species, including human pathogens. Typically, these systems consist of two genes in an operon which encodes a stable toxin disrupting essential cellular processes and a labile antitoxin preventing toxicity. Regulation of type II TA system in which both components are proteins, relies on proteolysis. In this paper, we outline the significant features of antitoxin proteins important for proteolysis. We present examples of best known processes of antitoxin degradation by specific proteases mainly in Escherichia coli, but are also included intensively studied systems from other bacteria. The effect of environmental conditions on regulation and activity of TA systems and on consequences of proteolytic activity are discussed.
Topics: Antitoxins; Bacterial Toxins; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Models, Molecular; Operon; Plasmids; Protein Stability; Proteolysis
PubMed: 23396045
DOI: 10.1016/j.plasmid.2013.01.007 -
Toxins Apr 2017Protein translation is the most common target of toxin-antitoxin system (TA) toxins. Sequence-specific endoribonucleases digest RNA in a sequence-specific manner,... (Review)
Review
Protein translation is the most common target of toxin-antitoxin system (TA) toxins. Sequence-specific endoribonucleases digest RNA in a sequence-specific manner, thereby blocking translation. While past studies mainly focused on the digestion of mRNA, recent analysis revealed that toxins can also digest tRNA, rRNA and tmRNA. Purified toxins can digest single-stranded portions of RNA containing recognition sequences in the absence of ribosome in vitro. However, increasing evidence suggests that in vivo digestion may occur in association with ribosomes. Despite the prevalence of recognition sequences in many mRNA, preferential digestion seems to occur at specific positions within mRNA and also in certain reading frames. In this review, a variety of tools utilized to study the nuclease activities of toxins over the past 15 years will be reviewed. A recent adaptation of an RNA-seq-based technique to analyze entire sets of cellular RNA will be introduced with an emphasis on its strength in identifying novel targets and redefining recognition sequences. The differences in biochemical properties and postulated physiological roles will also be discussed.
Topics: Antitoxins; Bacterial Proteins; Bacterial Toxins; Base Sequence; Endoribonucleases; RNA
PubMed: 28420090
DOI: 10.3390/toxins9040140