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Nature Reviews. Microbiology May 2022Clostridioides difficile is a Gram-positive anaerobe that can cause a spectrum of disorders that range in severity from mild diarrhoea to fulminant colitis and/or death.... (Review)
Review
Clostridioides difficile is a Gram-positive anaerobe that can cause a spectrum of disorders that range in severity from mild diarrhoea to fulminant colitis and/or death. The bacterium produces up to three toxins, which are considered the major virulence factors in C. difficile infection. These toxins promote inflammation, tissue damage and diarrhoea. In this Review, we highlight recent biochemical and structural advances in our understanding of the mechanisms that govern host-toxin interactions. Understanding how C. difficile toxins affect the host forms a foundation for developing novel strategies for treatment and prevention of C. difficile infection.
Topics: Antitoxins; Bacterial Proteins; Bacterial Toxins; Clostridioides difficile; Diarrhea; Humans
PubMed: 34837014
DOI: 10.1038/s41579-021-00660-2 -
Nature Dec 2022Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages. Similar to how eukaryotic innate immune systems...
Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages. Similar to how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns (PAMPs), many bacterial immune systems that respond to bacteriophage infection require phage-specific triggers to be activated. However, the identities of such triggers and the sensing mechanisms remain largely unknown. Here we identify and investigate the anti-phage function of CapRel, a fused toxin-antitoxin system that protects Escherichia coli against diverse phages. Using genetic, biochemical and structural analyses, we demonstrate that the C-terminal domain of CapRel regulates the toxic N-terminal region, serving as both antitoxin and phage infection sensor. Following infection by certain phages, newly synthesized major capsid protein binds directly to the C-terminal domain of CapRel to relieve autoinhibition, enabling the toxin domain to pyrophosphorylate tRNAs, which blocks translation to restrict viral infection. Collectively, our results reveal the molecular mechanism by which a bacterial immune system directly senses a conserved, essential component of phages, suggesting a PAMP-like sensing model for toxin-antitoxin-mediated innate immunity in bacteria. We provide evidence that CapRels and their phage-encoded triggers are engaged in a 'Red Queen conflict', revealing a new front in the intense coevolutionary battle between phages and bacteria. Given that capsid proteins of some eukaryotic viruses are known to stimulate innate immune signalling in mammalian hosts, our results reveal a deeply conserved facet of immunity.
Topics: Animals; Antitoxins; Bacteriophages; Capsid Proteins; Escherichia coli; Eukaryota; Pathogen-Associated Molecular Pattern Molecules; Immunity, Innate
PubMed: 36385533
DOI: 10.1038/s41586-022-05444-z -
BMB Reports Dec 2020Bacterial endoribonuclease toxins belong to a protein family that inhibits bacterial growth by degrading mRNA or rRNA sequences. The toxin genes are organized in pairs... (Review)
Review
Bacterial endoribonuclease toxins belong to a protein family that inhibits bacterial growth by degrading mRNA or rRNA sequences. The toxin genes are organized in pairs with its cognate antitoxins in the chromosome and thus the activities of the toxins are antagonized by antitoxin proteins or RNAs during active translation. In response to a variety of cellular stresses, the endoribonuclease toxins appear to be released from antitoxin molecules via proteolytic cleavage of antitoxin proteins or preferential degradation of antitoxin RNAs and cleave a diverse range of mRNA or rRNA sequences in a sequence-specific or codon-specific manner, resulting in various biological phenomena such as antibiotic tolerance and persister cell formation. Given that substrate specificity of each endoribonuclease toxin is determined by its structure and the composition of active site residues, we summarize the biology, structure, and substrate specificity of the updated bacterial endoribonuclease toxins. [BMB Reports 2020; 53(12): 611-621].
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; Endoribonucleases; Gene Expression Regulation, Bacterial; RNA, Messenger; Substrate Specificity
PubMed: 33148377
DOI: 10.5483/BMBRep.2020.53.12.203 -
Microbiological Research Nov 2022Toxin-antitoxin (TA) systems, composed of a stable toxin and a cognate unstable antitoxin, are ubiquitous in the genomes of bacteria and archaea. Under suitable growth... (Review)
Review
Toxin-antitoxin (TA) systems, composed of a stable toxin and a cognate unstable antitoxin, are ubiquitous in the genomes of bacteria and archaea. Under suitable growth conditions, an antitoxin prevents its cognate toxin from inducing toxicity; nonetheless, under stress or plasmid loss, it is either rapidly degraded or downregulated, thereby freeing the toxin to exert its activity toward various targets. Currently, TA systems are classified into eight types based on the nature and mode of action of antitoxins. TA expression is tightly regulated at multiple levels. These systems have various biological roles, including genetic element maintenance, virulence, stress resistance, and phage inhibition. Because of the toxic property of toxins, TA systems have been exploited for biotechnological (e.g., DNA cloning, plasmid maintenance, and counterselection) and medical (e.g., antibacterial drugs, antivirals, and anticancer therapies) applications. Herein, we provided an updated overview of TA systems by focusing on their classification, biological roles, and applications. We also described recent advances in research on TA systems and discussed research perspectives in this field.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Plasmids; Toxin-Antitoxin Systems
PubMed: 35969944
DOI: 10.1016/j.micres.2022.127159 -
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 -
Journal of Bacteriology Mar 2020Type II toxin-antitoxin (TA) systems are small genetic elements composed of a toxic protein and its cognate antitoxin protein, the latter counteracting the toxicity of... (Review)
Review
Type II toxin-antitoxin (TA) systems are small genetic elements composed of a toxic protein and its cognate antitoxin protein, the latter counteracting the toxicity of the former. While TA systems were initially discovered on plasmids, functioning as addiction modules through a phenomenon called postsegregational killing, they were later shown to be massively present in bacterial chromosomes, often in association with mobile genetic elements. Extensive research has been conducted in recent decades to better understand the physiological roles of these chromosomally encoded modules and to characterize the conditions leading to their activation. The diversity of their proposed roles, ranging from genomic stabilization and abortive phage infection to stress modulation and antibiotic persistence, in conjunction with the poor understanding of TA system regulation, resulted in the generation of simplistic models, often refuted by contradictory results. This review provides an epistemological and critical retrospective on TA modules and highlights fundamental questions concerning their roles and regulations that still remain unanswered.
Topics: Antitoxins; Bacterial Toxins; Biological Evolution; Genetic Association Studies; Genome, Bacterial; Phenotype; Toxin-Antitoxin Systems
PubMed: 31932311
DOI: 10.1128/JB.00763-19 -
Frontiers in Cellular and Infection... 2021The dynamic host environment presents a significant hurdle that pathogenic bacteria must overcome to survive and cause diseases. Consequently, these organisms have... (Review)
Review
The dynamic host environment presents a significant hurdle that pathogenic bacteria must overcome to survive and cause diseases. Consequently, these organisms have evolved molecular mechanisms to facilitate adaptation to environmental changes within the infected host. Small RNAs (sRNAs) have been implicated as critical regulators of numerous pathways and systems in pathogenic bacteria, including that of bacterial Toxin-Antitoxin (TA) systems. TA systems are typically composed of two factors, a stable toxin, and a labile antitoxin which functions to protect against the potentially deleterious activity of the associated toxin. Of the six classes of bacterial TA systems characterized to date, the toxin component is always a protein. Type I and Type III TA systems are unique in that the antitoxin in these systems is an RNA molecule, whereas the antitoxin in all other TA systems is a protein. Though hotly debated, the involvement of TA systems in bacterial physiology is recognized by several studies, with the Type II TA system being the most extensively studied to date. This review focuses on RNA-regulated TA systems, highlighting the role of Type I and Type III TA systems in several pathogenic bacteria.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; RNA; Toxin-Antitoxin Systems
PubMed: 34084755
DOI: 10.3389/fcimb.2021.661026 -
Toxins Feb 2023Toxin-antitoxin (TA) systems are typically composed of a stable toxin and a labile antitoxin; the latter counteracts the toxicity of the former under suitable... (Review)
Review
Toxin-antitoxin (TA) systems are typically composed of a stable toxin and a labile antitoxin; the latter counteracts the toxicity of the former under suitable conditions. TA systems are classified into eight types based on the nature and molecular modes of action of the antitoxin component so far. The 10 pairs of TA systems discovered and experimentally characterised in are type II TA systems. Type II TA systems have various physiological functions, such as virulence and biofilm formation, protection host against antibiotics, persistence, plasmid maintenance, and prophage production. Here, we review the type II TA systems of , focusing on their biological functions and regulatory mechanisms, providing potential applications for the novel drug design.
Topics: Pseudomonas aeruginosa; Escherichia coli; Toxin-Antitoxin Systems; Toxins, Biological; Antitoxins; Bacterial Proteins
PubMed: 36828478
DOI: 10.3390/toxins15020164 -
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 -
Pathogens and Disease Mar 2016Most bacterial toxins derived from chromosomally encoded toxin-antitoxin (TA) systems that have been studied to date appear to protect cells from relatively short pulses... (Review)
Review
Most bacterial toxins derived from chromosomally encoded toxin-antitoxin (TA) systems that have been studied to date appear to protect cells from relatively short pulses of stress by triggering a reversible state of growth arrest. In contrast to many bacterial toxins that are produced as defense mechanisms and secreted from their hosts, TA toxins exert their protective effect from within the cell that produces them. TA toxin-mediated growth arrest is most frequently achieved through their ability to selectively cleave RNA species that participate in protein synthesis. Until very recently, it was thought that the primary conduit for toxin-mediated translation inhibition was cleavage of a single class of RNA, mRNA, thus depleting transcripts and precluding production of essential proteins. This minireview focuses on how the development and implementation of a specialized RNA-seq method to study Mycobacterium tuberculosis TA systems enabled the identification of unexpected RNA targets for toxins, i.e. a handful of tRNAs that are cleaved into tRNA halves. Our result brings to light a new perspective on how these toxins may act in this pathogen and uncovers a striking parallel to signature features of the eukaryotic stress response.
Topics: Animals; Antitoxins; Bacterial Toxins; Colicins; Gene Expression Regulation, Bacterial; Humans; Inverted Repeat Sequences; Mycobacterium tuberculosis; Nucleic Acid Conformation; RNA, Bacterial; RNA, Transfer; Ribonuclease, Pancreatic; Sequence Analysis, RNA; Stress, Physiological; Tuberculosis
PubMed: 26657107
DOI: 10.1093/femspd/ftv117