Toxin-antitoxin systems: reversible toxicity.

Toxin-antitoxin (TA) systems encoded on the plasmids and chromosomes of bacteria are emerging as key players in stress adaptation. In particular, they have been implicated in the induction of persisters non-growing cells that can evade antibiotic exposure. TA toxins operate by a diverse range of mechanisms, either destructive or conservative, leading to the reversible growth arrest of bacterial cells. Whilst the molecular mechanisms of intoxication are now well understood, we still have very little information on how corrupted cells reawaken. Alongside the phenomenon of conditional cooperativity, new evidence suggests that the effects of some TA toxins can be reversed, allowing non-growing cells to be detoxified and growth to resume.

[1]  Thomas K. Wood,et al.  Protein Translation and Cell Death: The Role of Rare tRNAs in Biofilm Formation and in Activating Dormant Phage Killer Genes , 2008, PloS one.

[2]  A. Cheung,et al.  Overexpression of MazFSa in Staphylococcus aureus Induces Bacteriostasis by Selectively Targeting mRNAs for Cleavage , 2009, Journal of bacteriology.

[3]  K. Gerdes,et al.  Ectopic production of VapCs from Enterobacteria inhibits translation and trans‐activates YoeB mRNA interferase , 2009, Molecular microbiology.

[4]  R. Shoeman,et al.  A Novel Mechanism of Programmed Cell Death in Bacteria by Toxin–Antitoxin Systems Corrupts Peptidoglycan Synthesis , 2011, PLoS biology.

[5]  Rebecca Page,et al.  Toxin-antitoxin systems in bacterial growth arrest and persistence. , 2016, Nature chemical biology.

[6]  Jan Danckaert,et al.  A General Model for Toxin-Antitoxin Module Dynamics Can Explain Persister Cell Formation in E. coli , 2013, PLoS Comput. Biol..

[7]  M. Couturier,et al.  Cell killing by the F plasmid CcdB protein involves poisoning of DNA-topoisomerase II complexes. , 1992, Journal of molecular biology.

[8]  N. Zenkin,et al.  Molecular mechanism of bacterial persistence by HipA. , 2013, Molecular cell.

[9]  K. Gerdes,et al.  Toxin-antitoxin loci as stress-response-elements: ChpAK/MazF and ChpBK cleave translated RNAs and are counteracted by tmRNA. , 2003, Journal of molecular biology.

[10]  K. Gerdes,et al.  Bacterial persistence by RNA endonucleases , 2011, Proceedings of the National Academy of Sciences.

[11]  H. Engelberg-Kulka,et al.  Escherichia coli MazF Leads to the Simultaneous Selective Synthesis of Both “Death Proteins” and “Survival Proteins” , 2009, PLoS genetics.

[12]  N. Iqbal,et al.  Comprehensive Functional Analysis of the 18 Vibrio cholerae N16961 Toxin-Antitoxin Systems Substantiates Their Role in Stabilizing the Superintegron , 2015, Journal of bacteriology.

[13]  J. Beirlant,et al.  Obg and Membrane Depolarization Are Part of a Microbial Bet-Hedging Strategy that Leads to Antibiotic Tolerance. , 2015, Molecular cell.

[14]  K. Gerdes.  Hypothesis: type I toxin–antitoxin genes enter the persistence field—a feedback mechanism explaining membrane homoeostasis , 2016, Philosophical Transactions of the Royal Society B: Biological Sciences.

[15]  D. Helinski,et al.  and interaction with the ParD antitoxin protein . Plasmid RK 2 toxin protein ParE : purification , 1996 .

[16]  A. Bravo,et al.  Killing of Escherichia coli cells modulated by components of the stability system ParD of plasmid R1 , 1988, Molecular and General Genetics MGG.

[17]  Ming Ouyang,et al.  Clostridium difficile MazF Toxin Exhibits Selective, Not Global, mRNA Cleavage , 2012, Journal of bacteriology.

[18]  K. Gerdes,et al.  Enteric virulence associated protein VapC inhibits translation by cleavage of initiator tRNA , 2011, Proceedings of the National Academy of Sciences.

[19]  M. Inouye,et al.  Characterization of YafO, an Escherichia coli Toxin* , 2009, The Journal of Biological Chemistry.

[20]  M. Inouye,et al.  Interference of mRNA Function by Sequence-specific Endoribonuclease PemK* , 2004, Journal of Biological Chemistry.

[21]  Anastasia Mylona,et al.  A Salmonella Toxin Promotes Persister Formation through Acetylation of tRNA , 2016, Molecular cell.

[22]  Keith E. Weaver,et al.  The par toxin-antitoxin system from Enterococcus faecalis plasmid pAD1 and its chromosomal homologs , 2012, RNA biology.

[23]  B. C. M. Ramisetty,et al.  Escherichia coli MazEF toxin‐antitoxin system does not mediate programmed cell death , 2016, Journal of basic microbiology.

[24]  K. Gerdes,et al.  Adenylylation of Gyrase and Topo IV by FicT Toxins Disrupts Bacterial DNA Topology. , 2015, Cell reports.

[25]  T. Miki,et al.  Partner switching mechanisms in inactivation and rejuvenation of Escherichia coli DNA gyrase by F plasmid proteins LetD (CcdB) and LetA (CcdA). , 1996, Journal of molecular biology.

[26]  D. Tollervey,et al.  VapCs of Mycobacterium tuberculosis cleave RNAs essential for translation , 2016, Nucleic Acids Research.

[27]  M. Inouye,et al.  The mRNA interferases, MazF‐mt3 and MazF‐mt7 from Mycobacterium tuberculosis target unique pentad sequences in single‐stranded RNA , 2008, Molecular microbiology.

[28]  Suman Kapoor,et al.  Crucial contribution of the multiple copies of the initiator tRNA genes in the fidelity of tRNAfMet selection on the ribosomal P-site in Escherichia coli , 2010, Nucleic Acids Res..

[29]  K. Gerdes,et al.  Molecular Mechanisms Underlying Bacterial Persisters , 2014, Cell.

[30]  K. Gerdes,et al.  RelE, a global inhibitor of translation, is activated during nutritional stress , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  L. Wyns,et al.  The F plasmid CcdB protein induces efficient ATP-dependent DNA cleavage by gyrase. , 1993, Journal of molecular biology.

[32]  L. Van Melderen,et al.  New toxins homologous to ParE belonging to three‐component toxin–antitoxin systems in Escherichia coli O157:H7 , 2010, Molecular microbiology.

[33]  E. Rotem,et al.  HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase , 2013, Nature Communications.

[34]  C. Dunham,et al.  Mechanisms of Toxin Inhibition and Transcriptional Repression by Escherichia coli DinJ-YafQ* , 2014, The Journal of Biological Chemistry.

[35]  D. Brodersen,et al.  Cut to the chase--Regulating translation through RNA cleavage. , 2015, Biochimie.

[36]  T. Wood,et al.  Toxin MqsR cleaves single‐stranded mRNA with various 5' ends , 2016, MicrobiologyOpen.

[37]  Måns Ehrenberg,et al.  The Bacterial Toxin RelE Displays Codon-Specific Cleavage of mRNAs in the Ribosomal A Site , 2003, Cell.

[38]  Martin Overgaard,et al.  Messenger RNA interferase RelE controls relBE transcription by conditional cooperativity , 2008, Molecular microbiology.

[39]  T. Ogura,et al.  Mini-F plasmid genes that couple host cell division to plasmid proliferation. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. Pogliano,et al.  ParE toxin encoded by the broad‐host‐range plasmid RK2 is an inhibitor of Escherichia coli gyrase , 2002, Molecular microbiology.

[41]  A. Garcia-Pino,et al.  The Fic protein Doc uses an inverted substrate to phosphorylate and inactivate EF-Tu , 2013, Nature chemical biology.

[42]  Mitsuhiko Ikura,et al.  MazF cleaves cellular mRNAs specifically at ACA to block protein synthesis in Escherichia coli. , 2003, Molecular cell.

[43]  Jonathan W. Cruz,et al.  tRNA is a new target for cleavage by a MazF toxin , 2016, Nucleic acids research.

[44]  F. García-del Portillo,et al.  Distinct type I and type II toxin-antitoxin modules control Salmonella lifestyle inside eukaryotic cells , 2015, Scientific Reports.

[45]  Sujata Sharma,et al.  Structural and functional insights into peptidyl-tRNA hydrolase. , 2014, Biochimica et biophysica acta.

[46]  Peter C. Fineran,et al.  Selectivity and self-assembly in the control of a bacterial toxin by an antitoxic noncoding RNA pseudoknot , 2012, Proceedings of the National Academy of Sciences.

[47]  Torsten Herrmann,et al.  A Novel Type V TA System Where mRNA for Toxin GhoT is Cleaved by Antitoxin GhoS , 2012, Nature chemical biology.

[48]  R. Sauer,et al.  Role of a Peptide Tagging System in Degradation of Proteins Synthesized from Damaged Messenger RNA , 1996, Science.

[49]  K. Gerdes,et al.  RelE toxins from Bacteria and Archaea cleave mRNAs on translating ribosomes, which are rescued by tmRNA , 2003, Molecular microbiology.

[50]  Rolf Boelens,et al.  Interactions of Kid–Kis toxin–antitoxin complexes with the parD operator-promoter region of plasmid R1 are piloted by the Kis antitoxin and tuned by the stoichiometry of Kid–Kis oligomers , 2007, Nucleic acids research.

[51]  H. Engelberg-Kulka,et al.  An Escherichia coli chromosomal "addiction module" regulated by guanosine [corrected] 3',5'-bispyrophosphate: a model for programmed bacterial cell death. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Simina Grigoriu,et al.  The Escherichia coli Toxin MqsR Destabilizes the Transcriptional Repression Complex Formed between the Antitoxin MqsA and the mqsRA Operon Promoter* , 2012, The Journal of Biological Chemistry.

[53]  L. Van Melderen,et al.  What Is the Benefit to Escherichia coli of Having Multiple Toxin-Antitoxin Systems in Its Genome? , 2007, Journal of bacteriology.

[54]  H. Afif,et al.  The ratio between CcdA and CcdB modulates the transcriptional repression of the ccd poison–antidote system , 2001, Molecular microbiology.

[55]  L. Wyns,et al.  Rejuvenation of CcdB-poisoned gyrase by an intrinsically disordered protein domain. , 2009, Molecular cell.

[56]  Kim Sneppen,et al.  Conditional cooperativity in toxin–antitoxin regulation prevents random toxin activation and promotes fast translational recovery , 2012, Nucleic acids research.

[57]  F. García-del Portillo,et al.  Toxin-antitoxins and bacterial virulence. , 2016, FEMS microbiology reviews.

[58]  Sophie Helaine,et al.  Bacterial persisters: formation, eradication, and experimental systems. , 2014, Trends in microbiology.

[59]  M. Inouye,et al.  YeeU enhances the bundling of cytoskeletal polymers of MreB and FtsZ, antagonizing the CbtA (YeeV) toxicity in Escherichia coli , 2012, Molecular microbiology.

[60]  Jonathan W. Cruz,et al.  Growth-regulating Mycobacterium tuberculosis VapC-mt4 toxin is an isoacceptor-specific tRNase , 2015, Nature Communications.

[61]  K. Gerdes,et al.  Mechanism of postsegregational killing by the hok gene product of the parB system of plasmid R1 and its homology with the relF gene product of the E. coli relB operon. , 1986, The EMBO journal.

[62]  K. Gerdes,et al.  HicA of Escherichia coli Defines a Novel Family of Translation-Independent mRNA Interferases in Bacteria and Archaea , 2008, Journal of bacteriology.

[63]  L. Morganti,et al.  VapC from the Leptospiral VapBC Toxin-Antitoxin Module Displays Ribonuclease Activity on the Initiator tRNA , 2014, PloS one.

[64]  M. Laub,et al.  A bacterial toxin inhibits DNA replication elongation through a direct interaction with the β sliding clamp. , 2013, Molecular cell.

[65]  J. Alonso,et al.  Plasmid copy-number control and better-than-random segregation genes of pSM19035 share a common regulator. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[66]  Anthony Maxwell,et al.  Vibrio cholerae ParE2 Poisons DNA Gyrase via a Mechanism Distinct from Other Gyrase Inhibitors* , 2010, The Journal of Biological Chemistry.

[67]  M. Inouye,et al.  Single protein production in living cells facilitated by an mRNA interferase. , 2005, Molecular cell.

[68]  David W. Holden,et al.  Internalization of Salmonella by Macrophages Induces Formation of Nonreplicating Persisters , 2014, Science.

[69]  Lode Wyns,et al.  Allostery and Intrinsic Disorder Mediate Transcription Regulation by Conditional Cooperativity , 2010, Cell.

[70]  S. Lory,et al.  Emergence of Pseudomonas aeruginosa Strains Producing High Levels of Persister Cells in Patients with Cystic Fibrosis , 2010, Journal of bacteriology.

[71]  D. Paulin,et al.  Enzymatic hydrolysis of N‐substituted aminoacyl‐tRNA , 1968, Proceedings of the National Academy of Sciences of the United States of America.