Heterologous Expression of Toxins from Bacterial Toxin-Antitoxin Systems in Eukaryotic Cells: Strategies and Applications
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| caption | Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes, one of which encodes a stable toxin and the other, its cognate labile antitoxin. Certain environmental and physiological cues trigger the degradation of the antitoxin, causing activation of the toxin, leading either to the death or stasis of the host cell. TA systems have a variety of functions in the bacterial cell, including acting as mediators of programmed cell death, the induction of a dormant state known as persistence and the stable maintenance of plasmids and other mobile genetic elements. Some bacterial TA systems are functional when expressed in eukaryotic cells and this has led to several innovative applications, which are the subject of this review. Here, we look at how bacterial TA systems have been utilized for the genetic manipulation of yeasts and other eukaryotes, for the containment of genetically modified organisms, and for the engineering of high expression eukaryotic cell lines. We also examine how TA systems have been adopted as an important tool in developmental biology research for the ablation of specific cells and the potential for utility of TA systems in antiviral and anticancer gene therapies. |
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| date | 2024-08-27 15:26:13 |
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| id | 12907 |
| institution | UniSZA |
| internalnotes | 1. Gerdes, K.; Christensen, S.K.; Løbner-Olesen, A. Prokaryotic toxin-antitoxin stress response loci. Nat. Rev. Microbiol. 2005, 3, 371–382. 2. Hayes, F.; van Melderen, L. Toxins-antitoxins: Diversity, evolution and function. Crit. Rev. Biochem. Mol. Biol. 2011, 46, 386–408. 3. Yamaguchi, Y.; Park, J.-H.; Inouye, M. Toxin-antitoxin systems in bacteria and archaea. Annu. Rev. Genet. 2011, 45, 61–79. 4. Goeders, N.; van Melderen, L. Toxin-antitoxin systems as multilevel interaction systems. Toxins 2014, 6, 304–324. 5. Hayes, F.; K ˛edzierska, B. Regulating toxin-antitoxin expression: Controlled detonation of intracellular molecular timebombs. Toxins 2014, 6, 337–358. 6. Yarmolinsky, M.B. Programmed cell death in bacterial populations. Science 1995, 267, 836–837. 7. Hayes, F. Toxins-antitoxins: Plasmid maintenance, programmed cell death, and cell cycle arrest. Science 2003, 301, 1496–1499. 8. Aizenman, E.; Engelberg-Kulka, H.; Glaser, G. An Escherichia coli chromosomal “addiction module” regulated by guanosine 31 ,51 -bispyrophosphate: A model for programmed bacterial cell death. Proc. Natl. Acad. Sci. USA 1996, 93, 6059–6063. 9. Engelberg-Kulka, H.; Glaser, G. Addiction modules and programmed cell death and antideath in bacterial cultures. Annu. Rev. Microbiol. 1999, 53, 43–70. 10. Engelberg-Kulka, H.; Amitai, S.; Kolodkin-Gal, I.; Hazan, R. Bacterial programmed cell death and multicellular behavior in bacteria. PLoS Genet. 2006, 2. 11. Pedersen, K.; Christensen, S.K.; Gerdes, K. Rapid induction and reversal of a bacteriostatic condition by controlled expression of toxins and antitoxins. Mol. Microbiol. 2002, 45, 501–510. 12. Christensen, S.K.; Mikkelsen, M.; Pedersen, K.; Gerdes, K. RelE, a global inhibitor of translation, is activated during nutritional stress. Proc. Natl. Acad. Sci. USA 2001, 98, 14328–14333. 13. Christensen, S.K.; Gerdes, K. RelE toxins from bacteria and Archaea cleave mRNAs on translating ribosomes, which are rescued by tmRNA. Mol. Microbiol. 2003, 48, 1389–1400. 14. Keren, I.; Shah, D.; Spoering, A.; Kaldalu, N.; Lewis, K. Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J. Bacteriol. 2004, 186, 8172–8180. 15. Lewis, K. Persister cells. Annu. Rev. Microbiol. 2010, 64, 357–372. 16. De Bast, M.S.; Mine, N.; van Melderen, L. Chromosomal toxin-antitoxin systems may act as antiaddiction modules. J. Bacteriol. 2008, 190, 4603–4809. 17. Hazan, R.; Engelberg-Kulka, H. Escherichia coli mazEF-mediated cell death as a defense mechanism that inhibits the spread of phage P1. Mol. Genet. Genomics 2004, 272, 227–234. 18. Blower, T.R.; Evans, T.J.; Przybilski, R.; Fineran, P.C.; Salmond, G.P.C. Viral evasion of a bacterial suicide system by RNA-based molecular mimicry enables infectious altruism. PLoS Genet. 2012, 8. 19. Unterholzner, S.J.; Poppenberger, B.; Rozhon, W. Toxin-antitoxin Systems: Biology, identification, and application. Mob. Genet. Elem. 2013, 3. 20. Szekeres, S.; Dauti, M.; Wilde, C.; Mazel, D.; Rowe-Magnus, D.A. Chromosomal toxin-antitoxin loci can diminish large-scale genome reductions in the absence of selection. Mol. Microbiol. 2007, 63, 1588–1605. 21. Wang, X.; Wood, T.K. Toxin-antitoxin systems influence biofilm and persister cell formation and the general stress response. Appl. Environ. Microbiol. 2011, 77, 5577–5583. 22. Mutschler, H.; Meinhart, A. ε/ζ Systems: Their role in resistance, virulence, and their potential for antibiotic development. J. Mol. Med. 2011, 89, 1183–1194. 23. Bertram, R.; Schuster, C.F. Post-transcriptional regulation of gene expression in bacterial pathogens by toxin-antitoxin systems. Front. Cell. Infect. Microbiol. 2014, 4. 24. Ren, D.; Walker, A.N.; Daines, D.A. Toxin-antitoxin loci vapBC-1 and vapXD contribute to survival and virulence in nontypeable Haemophilus influenzae. BMC Microbiol. 2012, 12. 25. Fozo, E.M.; Hemm, M.R.; Storz, G. Small toxic proteins and the antisense RNAs that repress them. Microbiol. Mol. Biol. Rev. 2008, 72, 579–589. 26. Blower, T.R.; Short, F.L.; Rao, F.; Mizuguchi, K.; Pei, X.Y.; Fineran, P.C.; Luisi, B.F.; Salmond, G.P.C. Identification and classification of bacterial Type III toxin-antitoxin systems encoded in chromosomal and plasmid genomes. Nucleic Acids Res. 2012, 40, 6158–6173. 27. Masuda, H.; Tan, Q.; Awano, N.; Wu, K.-P.; Inouye, M. YeeU enhances the bundling of cytoskeletal polymers of MreB and FtsZ, antagonizing the CbtA (YeeV) toxicity in Escherichia coli. Mol. Microbiol. 2012, 84, 979–989. 28. Wang, X.; Lord, D.M.; Cheng, H.-Y.; Osbourne, D.O.; Hong, S.H.; Sanchez-Torres, V.; Quiroga, C.; Zheng, K.; Herrmann, T.; Peti, W.; et al. A new type V toxin-antitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS. Nat. Chem. Biol. 2012, 8, 855–861. 29. Markovski, M.; Wickner, S. Preventing bacterial suicide: A novel toxin-antitoxin strategy. Mol. Cell 2013, 52, 611–612. 30. Aakre, C.D.; Phung, T.N.; Huang, D.; Laub, M.T. A bacterial toxin inhibits DNA replication elongation through a direct interaction with the β sliding clamp. Mol. Cell 2013, 52, 617–628. 31. Chan, W.T.; Balsa, D.; Espinosa, M. One cannot rule them all: Are bacterial toxins-antitoxins druggable? FEMS Microbiol. Rev. 2015, 39, 522–540. 32. Stieber, D.; Gabant, P.; Szpirer, C.Y. The art of selective killing: Plasmid toxin/antitoxin systems and their technological applications. Biotechniques 2008, 45, 344–346. 33. Kristoffersen, P.; Jensen, G.B.; Gerdes, K.; Piskur, J. Bacterial toxin-antitoxin gene system as containment control in yeast cells. Appl. Environ. Microbiol. 2000, 66, 5524–5526. 34. Yamamoto, T.M.; Gerdes, K.; Tunnacliffe, A. Bacterial toxin RelE induces apoptosis in human cells. FEBS Lett. 2002, 519, 191–194. 35. De la Cueva-Méndez, G.; Mills, A.D.; Clay-Farrace, L.; Díaz-Orejas, R.; Laskey, R.A. Regulatable killing of eukaryotic cells by the prokaryotic proteins Kid and Kis. EMBO J. 2003, 22, 246–251. 36. García, J.L.; Díaz, E. Plasmids as tools for containment. Microbiol. Spectr. 2014, 2. 37. Torres, B.; Jaenecke, S.; Timmis, K.N.; García, J.L.; Díaz, E. A dual lethal system to enhance containment of recombinant micro-organisms. Microbiology 2003, 149, 3595–3601. 38. Mandell, D.J.; Lajoie, M.J.; Mee, M.T.; Takeuchi, R.; Kuznetsov, G.; Norville, J.E.; Gregg, C.J.; Stoddard, B.L.; Church, G.M. Biocontainment of genetically modified organisms by synthetic protein design. Nature 2015, 518, 55–60. 39. Rovner, A.J.; Haimovich, A.D.; Katz, S.R.; Li, Z.; Grome, M.W.; Gassaway, B.M.; Amiram, M.; Patel, J.R.; Gallagher, R.R.; Rinehart, J.; et al. Recoded organisms engineered to depend on synthetic amino acids. Nature 2015, 518, 89–93. 40. Kroll, J.; Klinter, S.; Schneider, C.; Voss, I.; Steinbüchel, A. Plasmid addiction systems: Perspectives and applications in biotechnology. Microb. Biotechnol. 2010, 3, 634–657. 41. Zielenkiewicz, U.; Kowalewska, M.; Kaczor, C.; Ceglowski, P. In vivo interactions between toxin-antitoxin proteins epsilon and zeta of streptococcal plasmid pSM19035 in Saccharomyces cerevisiae. J. Bacteriol. 2009, 191, 3677–3684. 42. Muñoz-Gómez, A.J.; Lemonnier, M.; Santos-Sierra, S.; Berzal-Herranz, A.; Díaz-Orejas, R. RNase/anti-RNase activities of the bacterial parD toxin-antitoxin system. J. Bacteriol. 2005, 187, 3151–3157. 43. Mutschler, H.; Gebhardt, M.; Shoeman, R.L.; Meinhart, A. A novel mechanism of programmed cell death in bacteria by toxin-antitoxin systems corrupts peptidoglycan synthesis. PLoS Biol. 2011, 9. 44. Balan, A.; Schenberg, A.C.G. A conditional suicide system for Saccharomyces cerevisiae relying on the intracellular production of the Serratia marcescens nuclease. Yeast 2005, 22, 203–212. 45. Cabib, E.; Farkas, V.; Kosik, O.; Blanco, N.; Arroyo, J.; McPhie, P. Assembly of the yeast cell wall: Crh1p and Crh2p act as transglycosylases in vivo and in vitro. J. Biol. Chem. 2008, 283, 29859–29872. 46. Chan, C.T.Y.; Lee, J.W.; Cameron, D.E.; Bashor, C.J.; Collins, J.J. “Deadman” and “Passcode” microbial kill switches for bacterial containment. Nat. Chem. Biol. 2016, 12, 82–86. 47. Yang, J.; Jiang, W.; Yang, S. MazF as a counter-selectable marker for unmarked genetic modification of Pichia pastoris. FEMS Yeast Res. 2009, 9, 600–609. 48. Chen, Z.; Sun, H.; Li, P.; He, N.; Zhu, T.; Li, Y. Enhancement of the gene targeting efficiency of non-conventional yeasts by increasing genetic redundancy. PLoS ONE 2013, 8. 49. Murphy, D.J. Improving containment strategies in biopharming. Plant Biotechnol. J. 2007, 5, 555–569. 50. Kamle, S.; Ali, S. Genetically modified crops: Detection strategies and biosafety issues. Gene 2013, 522, 123–132. 51. Sang, Y.; Millwood, R.J.; Neal Stewart, C., Jr. Gene use restriction technologies for transgenic plant bioconfinement. Plant Biotechnol. J. 2013, 11, 649–658. 52. Zhang, X.; Wang, D.; Zhao, S.; Shen, Z. A double built-in containment strategy for production of recombinant proteins in transgenic rice. PLoS ONE 2014, 9. 53. Lombardo, L. Genetic use restriction technologies: A review. Plant Biotechnol. J. 2014, 12, 995–1005. 54. Kempe, K.; Rubtsova, M.; Gils, M. Split-gene system for hybrid wheat seed production. Proc. Natl. Acad. Sci. USA 2014, 111, 9097–9102. 55. Medina, M.; Roque, E.; Pineda, B.; Cañas, L.; Rodriguez-Concepción, M.; Beltrán, J.P.; Gómez-Mena, C. Early anther ablation triggers parthenocarpic fruit development in tomato. Plant Biotechnol. J. 2013, 11, 770–779. 56. Ulyanova, V.; Vershinina, V.; Ilinskaya, O. Barnase and binase: Twins with distinct fates. FEBS J. 2011, 278, 3633–3643. 57. Mariani, C.; de Beuckeleer, M.; Truettner, J.; Leemans, J.; Goldberg, R.B. Induction of male sterility in plants by a chimaeric ribonuclease gene. Nature 1990, 347, 737–741. 58. Goldman, M.H.; Goldberg, R.B.; Mariani, C. Female sterile tobacco plants are produced by stigma-specific cell ablation. EMBO J. 1994, 13, 2976–2984. 59. Beals, T.P.; Goldberg, R.B. A novel cell ablation strategy blocks tobacco anther dehiscence. Plant Cell 1997, 9, 1527–1545. 60. Gardner, N.; Felsheim, R.; Smith, A.G. Production of male- and female-sterile plants through reproductive tissue ablation. J. Plant Physiol. 2009, 166, 871–881. 61. Kobayashi, K.; Munemura, I.; Hinata, K.; Yamamura, S. Bisexual sterility conferred by the differential expression of barnase and barstar: A simple and efficient method of transgene containment. Plant Cell Rep. 2006, 25, 1347–1354. 62. Bisht, N.C.; Jagannath, A.; Augustine, R.; Burma, P.K.; Gupta, V.; Pradhan, A.K.; Pental, D. Effective restoration of male-sterile (barnase) lines requires overlapping and higher levels of barstar expression: A multi-generation field analysis in Brassica juncea. J. Plant Biochem. Biotechnol. 2014, 24, 393–399. 63. Millwood, R.J.; Moon, H.S.; Poovaiah, C.R.; Muthukumar, B.; Rice, J.H.; Abercrombie, J.M.; Abercrombie, L.L.; Green, W.D.; Stewart, C.N. Engineered selective plant male sterility through pollen-specific expression of the EcoRI restriction endonuclease. Plant Biotechnol. J. 2015. 64. Iida, S.; Terada, R. Modification of endogenous natural genes by gene targeting in rice and other higher plants. Plant Mol. Biol. 2005, 59, 205–219. 65. Bakar, F.A.; Yeo, C.C.; Harikrishna, J.A. Expression of the Streptococcus pneumoniae yoeB chromosomal toxin gene causes cell death in the model plant Arabidopsis thaliana. BMC Biotechnol. 2015, 15. 66. Brand, L.; Horler, M.; Nuesch, E.; Vassalli, S.; Barrell, P.; Yang, W.; Jefferson, R.A.; Grossniklaus, U.; Curtis, M.D. A versatile and reliable two-component system for tissue-specific gene induction in arabidopsis. Plant Physiol. 2006, 141, 1194–1204. 67. Borgen, B.H.; Thangstad, O.P.; Ahuja, I.; Rossiter, J.T.; Bones, A.M. Removing the mustard oil bomb from seeds: Transgenic ablation of myrosin cells in oilseed rape (Brassica napus) produces MINELESS seeds. J. Exp. Bot. 2010, 61, 1683–1697. 68. Nieto, C.; Cherny, I.; Khoo, S.K.; de Lacoba, M.G.; Chan, W.T.; Yeo, C.C.; Gazit, E.; Espinosa, M. The yefM-yoeB toxin-antitoxin systems of Escherichia coli and Streptococcus pneumoniae: Functional and structural correlation. J. Bacteriol. 2007, 189, 1266–1278. 69. Zuo, J.; Niu, Q.-W.; Chua, N.-H. An estrogen receptor-based transactivator XVE mediates highly inducible gene expression in transgenic plants. Plant J. 2000, 24, 265–273. 70. Slanchev, K.; Stebler, J.; de la Cueva-Méndez, G.; Raz, E. Development without germ cells: The role of the germ line in zebrafish sex differentiation. Proc. Natl. Acad. Sci. USA 2005, 102, 4074–4079. 71. Shimazu, T.; Degenhardt, K.; Nur-E-Kamal, A.; Zhang, J.; Yoshida, T.; Zhang, Y.; Mathew, R.; White, E.; Inouye, M. NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition. Genes Dev. 2007, 21, 929–941. 72. Browne, S.M.; Al-Rubeai, M. Selection methods for high-producing mammalian cell lines. Trends Biotechnol. 2007, 25, 425–432. 73. Nehlsen, K.; Herrmann, S.; Zauers, J.; Hauser, H.; Wirth, D. Toxin-antitoxin based transgene expression in mammalian cells. Nucleic Acids Res. 2010, 38. 74. Chono, H.; Matsumoto, K.; Tsuda, H.; Saito, N.; Lee, K.; Kim, S.; Shibata, H.; Ageyama, N.; Terao, K.; Yasutomi, Y.; et al. Acquisition of HIV-1 resistance in T lymphocytes using an ACA-specific E. coli mRNA interferase. Hum. Gene Ther. 2011, 22, 35–43. 75. Zhang, Y.; Zhang, J.; Hoeflich, K.P.; Ikura, M.; Qing, G.; Inouye, M. MazF cleaves cellular mRNAs specifically at ACA to block protein synthesis in Escherichia coli. Mol. Cell 2003, 12, 913–923. 76. Chono, H.; Saito, N.; Tsuda, H.; Shibata, H.; Ageyama, N.; Terao, K.; Yasutomi, Y.; Mineno, J.; Kato, I. In vivo safety and persistence of endoribonuclease gene-transduced CD4+ T cells in cynomolgus macaques for HIV-1 gene therapy model. PLoS ONE 2011, 6. 77. Park, J.-H.; Yamaguchi, Y.; Inouye, M. Intramolecular regulation of the sequence-specific mRNA interferase activity of MazF fused to a MazE fragment with a linker cleavable by specific proteases. Appl. Environ. Microbiol. 2012, 78, 3794–3799. 78. Shapira, A.; Shapira, S.; Gal-Tanamy, M.; Zemel, R.; Tur-Kaspa, R.; Benhar, I. Removal of hepatitis C virus-infected cells by a zymogenized bacterial toxin. PLoS ONE 2012, 7. 79. De la Cueva-Méndez, G. Systems and Methods for Diminishing Cell Growth and Inducing Selective Killing of Target Cells. WO2013037504 A4, 7 June 2013. 80. Preston, M.A.; Pimentel, B.; Bermejo-Rodríguez, C.; Dionne, I.; Turnbull, A.; de la Cueva-Méndez, G. Repurposing a prokaryotic toxin-antitoxin system for the selective killing of oncogenically stressed human cells. ACS Synth. Biol. 2015. 81. Bravo, A.; de Torrontegui, G.; Díaz, R. Identification of components of a new stability system of plasmid R1, ParD, that is close to the origin of replication of this plasmid. Mol. Gen. Genet. 1987, 210, 101–110. 82. Yamaguchi, Y.; Inouye, M. Type II toxin-antitoxin loci: The mazEF Family. In Prokaryotic Toxin-Antitoxins; Gerdes, K., Ed.; Springer-Verlag: Berlin, Germnay, 2013; pp. 107–136. 83. Wieteska, Ł.; Skulimowski, A.; Cybula, M.; Szemraj, J. Toxins vapC and pasB from prokaryotic TA modules remain active in mammalian cancer cells. Toxins 2014, 6, 2948–2961. 84. De la Cueva-Méndez, G.; Pimentel, B. Biotechnological and medical exploitation of toxin-antitoxin genes and their components. In Prokaryotic Toxin-Antitoxins; Gerdes, K., Ed.; Springer: Berlin, Germany, 2013; pp. 341–360. 85. Llosa, M.; Zupan, J.; Baron, C.; Zambryski, P. The N- and C-terminal portions of the agrobacterium VirB1 protein independently enhance tumorigenesis. J. Bacteriol. 2000, 182, 3437–3445. 86. Draper, O.; César, C.E.; Machón, C.; de la Cruz, F.; Llosa, M. Site-specific recombinase and integrase activities of a conjugative relaxase in recipient cells. Proc. Natl. Acad. Sci. USA 2005, 102, 16385–16390. 87. Llosa, M.; Roy, C.; Dehio, C. Bacterial type IV secretion systems in human disease. Mol. Microbiol. 2009, 73, 141–151. 88. González-Prieto, C.; Agúndez, L.; Linden, R.M.; Llosa, M. HUH site-specific recombinases for targeted modification of the human genome. Trends Biotechnol. 2013, 31, 305–312 89. Gerdes, K. Prokaryotic Toxin-Antitoxins, 1st ed.; Springer-Verlag: Berlin, Germany, 2013 |
| originalfilename | 7214-01-FH02-FP-16-05618.pdf |
| person | Chew Chieng Yeo Fauziah Abu Bakar Wai Ting Chan Manuel Espinosa and Jennifer Ann Harikrishna |
| recordtype | oai_dc |
| resourceurl | https://intelek.unisza.edu.my/intelek/pages/view.php?ref=12907 |
| spelling | 12907 https://intelek.unisza.edu.my/intelek/pages/view.php?ref=12907 https://intelek.unisza.edu.my/intelek/pages/search.php?search=!collection407072 Restricted Document Article Journal application/pdf Adobe Acrobat Pro DC 20 Paper Capture Plug-in with ClearScan 18 1.6 Chew Chieng Yeo Fauziah Abu Bakar Wai Ting Chan Manuel Espinosa and Jennifer Ann Harikrishna 2024-08-27 15:26:13 Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes, one of which encodes a stable toxin and the other, its cognate labile antitoxin. Certain environmental and physiological cues trigger the degradation of the antitoxin, causing activation of the toxin, leading either to the death or stasis of the host cell. TA systems have a variety of functions in the bacterial cell, including acting as mediators of programmed cell death, the induction of a dormant state known as persistence and the stable maintenance of plasmids and other mobile genetic elements. Some bacterial TA systems are functional when expressed in eukaryotic cells and this has led to several innovative applications, which are the subject of this review. Here, we look at how bacterial TA systems have been utilized for the genetic manipulation of yeasts and other eukaryotes, for the containment of genetically modified organisms, and for the engineering of high expression eukaryotic cell lines. We also examine how TA systems have been adopted as an important tool in developmental biology research for the ablation of specific cells and the potential for utility of TA systems in antiviral and anticancer gene therapies. Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes one of which encodes a stable toxin and the other its cognate labile antitoxin. Certain environmental and physiological cues trigger the degradation of the antitoxin causing activation of the toxin leading either to the death or stasis of the host cell. TA systems have a variety of functions in the bacterial cell including acting as mediators of programmed cell death the induction of a dormant state known as persistence and the stable maintenance of plasmids and other mobile genetic elements. Some bacterial TA systems are functional when expressed in eukaryotic cells and this has led to several innovative applications which are the subject of this review. Here we look at how bacterial TA systems have been utilized for the genetic manipulation of yeasts and other eukaryotes for the containment of genetically modified organisms and for the engineering of high expression eukaryotic cell lines. We also examine how TA systems have been adopted as an important tool in developmental biology research for the ablation of specific cells and the potential for utility of TA systems in antiviral and anticancer gene therapies. 7214-01-FH02-FP-16-05618.pdf UniSZA Private Access Heterologous Expression of Toxins from Bacterial Toxin-Antitoxin Systems in Eukaryotic Cells: Strategies and Applications Strategies and Applications. Toxins Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes, one of which encodes a stable toxin and the other, its cognate labile antitoxin. Certain environmental and physiological cues trigger the degradation of the antitoxin, causing activation of the toxin, leading either to the death or stasis of the host cell. TA systems have a variety of functions in the bacterial cell, including acting as mediators of programmed cell death, the induction of a dormant state known as persistence and the stable maintenance of plasmids and other mobile genetic elements. Some bacterial TA systems are functional when expressed in eukaryotic cells and this has led to several innovative applications, which are the subject of this review. Here, we look at how bacterial TA systems have been utilized for the genetic manipulation of yeasts and other eukaryotes, for the containment of genetically modified organisms, and for the engineering of high expression eukaryotic cell lines. We also examine how TA systems have been adopted as an important tool in developmental biology research for the ablation of specific cells and the potential for utility of TA systems in antiviral and anticancer gene therapies. 8 2 1-16 1. Gerdes, K.; Christensen, S.K.; Løbner-Olesen, A. Prokaryotic toxin-antitoxin stress response loci. Nat. Rev. Microbiol. 2005, 3, 371–382. 2. Hayes, F.; van Melderen, L. Toxins-antitoxins: Diversity, evolution and function. Crit. Rev. Biochem. Mol. Biol. 2011, 46, 386–408. 3. Yamaguchi, Y.; Park, J.-H.; Inouye, M. Toxin-antitoxin systems in bacteria and archaea. Annu. Rev. Genet. 2011, 45, 61–79. 4. Goeders, N.; van Melderen, L. Toxin-antitoxin systems as multilevel interaction systems. Toxins 2014, 6, 304–324. 5. Hayes, F.; K ˛edzierska, B. Regulating toxin-antitoxin expression: Controlled detonation of intracellular molecular timebombs. Toxins 2014, 6, 337–358. 6. Yarmolinsky, M.B. Programmed cell death in bacterial populations. Science 1995, 267, 836–837. 7. Hayes, F. Toxins-antitoxins: Plasmid maintenance, programmed cell death, and cell cycle arrest. Science 2003, 301, 1496–1499. 8. Aizenman, E.; Engelberg-Kulka, H.; Glaser, G. An Escherichia coli chromosomal “addiction module” regulated by guanosine 31 ,51 -bispyrophosphate: A model for programmed bacterial cell death. Proc. Natl. Acad. Sci. USA 1996, 93, 6059–6063. 9. Engelberg-Kulka, H.; Glaser, G. Addiction modules and programmed cell death and antideath in bacterial cultures. Annu. Rev. Microbiol. 1999, 53, 43–70. 10. Engelberg-Kulka, H.; Amitai, S.; Kolodkin-Gal, I.; Hazan, R. Bacterial programmed cell death and multicellular behavior in bacteria. PLoS Genet. 2006, 2. 11. Pedersen, K.; Christensen, S.K.; Gerdes, K. Rapid induction and reversal of a bacteriostatic condition by controlled expression of toxins and antitoxins. Mol. Microbiol. 2002, 45, 501–510. 12. Christensen, S.K.; Mikkelsen, M.; Pedersen, K.; Gerdes, K. RelE, a global inhibitor of translation, is activated during nutritional stress. Proc. Natl. Acad. Sci. USA 2001, 98, 14328–14333. 13. Christensen, S.K.; Gerdes, K. RelE toxins from bacteria and Archaea cleave mRNAs on translating ribosomes, which are rescued by tmRNA. Mol. Microbiol. 2003, 48, 1389–1400. 14. Keren, I.; Shah, D.; Spoering, A.; Kaldalu, N.; Lewis, K. Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J. Bacteriol. 2004, 186, 8172–8180. 15. Lewis, K. Persister cells. Annu. Rev. Microbiol. 2010, 64, 357–372. 16. De Bast, M.S.; Mine, N.; van Melderen, L. Chromosomal toxin-antitoxin systems may act as antiaddiction modules. J. Bacteriol. 2008, 190, 4603–4809. 17. Hazan, R.; Engelberg-Kulka, H. Escherichia coli mazEF-mediated cell death as a defense mechanism that inhibits the spread of phage P1. Mol. Genet. Genomics 2004, 272, 227–234. 18. Blower, T.R.; Evans, T.J.; Przybilski, R.; Fineran, P.C.; Salmond, G.P.C. Viral evasion of a bacterial suicide system by RNA-based molecular mimicry enables infectious altruism. PLoS Genet. 2012, 8. 19. Unterholzner, S.J.; Poppenberger, B.; Rozhon, W. Toxin-antitoxin Systems: Biology, identification, and application. Mob. Genet. Elem. 2013, 3. 20. Szekeres, S.; Dauti, M.; Wilde, C.; Mazel, D.; Rowe-Magnus, D.A. Chromosomal toxin-antitoxin loci can diminish large-scale genome reductions in the absence of selection. Mol. Microbiol. 2007, 63, 1588–1605. 21. Wang, X.; Wood, T.K. Toxin-antitoxin systems influence biofilm and persister cell formation and the general stress response. Appl. Environ. Microbiol. 2011, 77, 5577–5583. 22. Mutschler, H.; Meinhart, A. ε/ζ Systems: Their role in resistance, virulence, and their potential for antibiotic development. J. Mol. Med. 2011, 89, 1183–1194. 23. Bertram, R.; Schuster, C.F. Post-transcriptional regulation of gene expression in bacterial pathogens by toxin-antitoxin systems. Front. Cell. Infect. Microbiol. 2014, 4. 24. Ren, D.; Walker, A.N.; Daines, D.A. Toxin-antitoxin loci vapBC-1 and vapXD contribute to survival and virulence in nontypeable Haemophilus influenzae. BMC Microbiol. 2012, 12. 25. Fozo, E.M.; Hemm, M.R.; Storz, G. Small toxic proteins and the antisense RNAs that repress them. Microbiol. Mol. Biol. Rev. 2008, 72, 579–589. 26. Blower, T.R.; Short, F.L.; Rao, F.; Mizuguchi, K.; Pei, X.Y.; Fineran, P.C.; Luisi, B.F.; Salmond, G.P.C. Identification and classification of bacterial Type III toxin-antitoxin systems encoded in chromosomal and plasmid genomes. Nucleic Acids Res. 2012, 40, 6158–6173. 27. Masuda, H.; Tan, Q.; Awano, N.; Wu, K.-P.; Inouye, M. YeeU enhances the bundling of cytoskeletal polymers of MreB and FtsZ, antagonizing the CbtA (YeeV) toxicity in Escherichia coli. Mol. Microbiol. 2012, 84, 979–989. 28. Wang, X.; Lord, D.M.; Cheng, H.-Y.; Osbourne, D.O.; Hong, S.H.; Sanchez-Torres, V.; Quiroga, C.; Zheng, K.; Herrmann, T.; Peti, W.; et al. A new type V toxin-antitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS. Nat. Chem. Biol. 2012, 8, 855–861. 29. Markovski, M.; Wickner, S. Preventing bacterial suicide: A novel toxin-antitoxin strategy. Mol. Cell 2013, 52, 611–612. 30. Aakre, C.D.; Phung, T.N.; Huang, D.; Laub, M.T. A bacterial toxin inhibits DNA replication elongation through a direct interaction with the β sliding clamp. Mol. Cell 2013, 52, 617–628. 31. Chan, W.T.; Balsa, D.; Espinosa, M. One cannot rule them all: Are bacterial toxins-antitoxins druggable? FEMS Microbiol. Rev. 2015, 39, 522–540. 32. Stieber, D.; Gabant, P.; Szpirer, C.Y. The art of selective killing: Plasmid toxin/antitoxin systems and their technological applications. Biotechniques 2008, 45, 344–346. 33. Kristoffersen, P.; Jensen, G.B.; Gerdes, K.; Piskur, J. Bacterial toxin-antitoxin gene system as containment control in yeast cells. Appl. Environ. Microbiol. 2000, 66, 5524–5526. 34. Yamamoto, T.M.; Gerdes, K.; Tunnacliffe, A. Bacterial toxin RelE induces apoptosis in human cells. FEBS Lett. 2002, 519, 191–194. 35. De la Cueva-Méndez, G.; Mills, A.D.; Clay-Farrace, L.; Díaz-Orejas, R.; Laskey, R.A. Regulatable killing of eukaryotic cells by the prokaryotic proteins Kid and Kis. EMBO J. 2003, 22, 246–251. 36. García, J.L.; Díaz, E. Plasmids as tools for containment. Microbiol. Spectr. 2014, 2. 37. Torres, B.; Jaenecke, S.; Timmis, K.N.; García, J.L.; Díaz, E. A dual lethal system to enhance containment of recombinant micro-organisms. Microbiology 2003, 149, 3595–3601. 38. Mandell, D.J.; Lajoie, M.J.; Mee, M.T.; Takeuchi, R.; Kuznetsov, G.; Norville, J.E.; Gregg, C.J.; Stoddard, B.L.; Church, G.M. Biocontainment of genetically modified organisms by synthetic protein design. Nature 2015, 518, 55–60. 39. Rovner, A.J.; Haimovich, A.D.; Katz, S.R.; Li, Z.; Grome, M.W.; Gassaway, B.M.; Amiram, M.; Patel, J.R.; Gallagher, R.R.; Rinehart, J.; et al. Recoded organisms engineered to depend on synthetic amino acids. Nature 2015, 518, 89–93. 40. Kroll, J.; Klinter, S.; Schneider, C.; Voss, I.; Steinbüchel, A. Plasmid addiction systems: Perspectives and applications in biotechnology. Microb. Biotechnol. 2010, 3, 634–657. 41. Zielenkiewicz, U.; Kowalewska, M.; Kaczor, C.; Ceglowski, P. In vivo interactions between toxin-antitoxin proteins epsilon and zeta of streptococcal plasmid pSM19035 in Saccharomyces cerevisiae. J. Bacteriol. 2009, 191, 3677–3684. 42. Muñoz-Gómez, A.J.; Lemonnier, M.; Santos-Sierra, S.; Berzal-Herranz, A.; Díaz-Orejas, R. RNase/anti-RNase activities of the bacterial parD toxin-antitoxin system. J. Bacteriol. 2005, 187, 3151–3157. 43. Mutschler, H.; Gebhardt, M.; Shoeman, R.L.; Meinhart, A. A novel mechanism of programmed cell death in bacteria by toxin-antitoxin systems corrupts peptidoglycan synthesis. PLoS Biol. 2011, 9. 44. Balan, A.; Schenberg, A.C.G. A conditional suicide system for Saccharomyces cerevisiae relying on the intracellular production of the Serratia marcescens nuclease. Yeast 2005, 22, 203–212. 45. Cabib, E.; Farkas, V.; Kosik, O.; Blanco, N.; Arroyo, J.; McPhie, P. Assembly of the yeast cell wall: Crh1p and Crh2p act as transglycosylases in vivo and in vitro. J. Biol. Chem. 2008, 283, 29859–29872. 46. Chan, C.T.Y.; Lee, J.W.; Cameron, D.E.; Bashor, C.J.; Collins, J.J. “Deadman” and “Passcode” microbial kill switches for bacterial containment. Nat. Chem. Biol. 2016, 12, 82–86. 47. Yang, J.; Jiang, W.; Yang, S. MazF as a counter-selectable marker for unmarked genetic modification of Pichia pastoris. FEMS Yeast Res. 2009, 9, 600–609. 48. Chen, Z.; Sun, H.; Li, P.; He, N.; Zhu, T.; Li, Y. Enhancement of the gene targeting efficiency of non-conventional yeasts by increasing genetic redundancy. PLoS ONE 2013, 8. 49. Murphy, D.J. Improving containment strategies in biopharming. Plant Biotechnol. J. 2007, 5, 555–569. 50. Kamle, S.; Ali, S. Genetically modified crops: Detection strategies and biosafety issues. Gene 2013, 522, 123–132. 51. Sang, Y.; Millwood, R.J.; Neal Stewart, C., Jr. Gene use restriction technologies for transgenic plant bioconfinement. Plant Biotechnol. J. 2013, 11, 649–658. 52. Zhang, X.; Wang, D.; Zhao, S.; Shen, Z. A double built-in containment strategy for production of recombinant proteins in transgenic rice. PLoS ONE 2014, 9. 53. Lombardo, L. Genetic use restriction technologies: A review. Plant Biotechnol. J. 2014, 12, 995–1005. 54. Kempe, K.; Rubtsova, M.; Gils, M. Split-gene system for hybrid wheat seed production. Proc. Natl. Acad. Sci. USA 2014, 111, 9097–9102. 55. Medina, M.; Roque, E.; Pineda, B.; Cañas, L.; Rodriguez-Concepción, M.; Beltrán, J.P.; Gómez-Mena, C. Early anther ablation triggers parthenocarpic fruit development in tomato. Plant Biotechnol. J. 2013, 11, 770–779. 56. Ulyanova, V.; Vershinina, V.; Ilinskaya, O. Barnase and binase: Twins with distinct fates. FEBS J. 2011, 278, 3633–3643. 57. Mariani, C.; de Beuckeleer, M.; Truettner, J.; Leemans, J.; Goldberg, R.B. Induction of male sterility in plants by a chimaeric ribonuclease gene. Nature 1990, 347, 737–741. 58. Goldman, M.H.; Goldberg, R.B.; Mariani, C. Female sterile tobacco plants are produced by stigma-specific cell ablation. EMBO J. 1994, 13, 2976–2984. 59. Beals, T.P.; Goldberg, R.B. A novel cell ablation strategy blocks tobacco anther dehiscence. Plant Cell 1997, 9, 1527–1545. 60. Gardner, N.; Felsheim, R.; Smith, A.G. Production of male- and female-sterile plants through reproductive tissue ablation. J. Plant Physiol. 2009, 166, 871–881. 61. Kobayashi, K.; Munemura, I.; Hinata, K.; Yamamura, S. Bisexual sterility conferred by the differential expression of barnase and barstar: A simple and efficient method of transgene containment. Plant Cell Rep. 2006, 25, 1347–1354. 62. Bisht, N.C.; Jagannath, A.; Augustine, R.; Burma, P.K.; Gupta, V.; Pradhan, A.K.; Pental, D. Effective restoration of male-sterile (barnase) lines requires overlapping and higher levels of barstar expression: A multi-generation field analysis in Brassica juncea. J. Plant Biochem. Biotechnol. 2014, 24, 393–399. 63. Millwood, R.J.; Moon, H.S.; Poovaiah, C.R.; Muthukumar, B.; Rice, J.H.; Abercrombie, J.M.; Abercrombie, L.L.; Green, W.D.; Stewart, C.N. Engineered selective plant male sterility through pollen-specific expression of the EcoRI restriction endonuclease. Plant Biotechnol. J. 2015. 64. Iida, S.; Terada, R. Modification of endogenous natural genes by gene targeting in rice and other higher plants. Plant Mol. Biol. 2005, 59, 205–219. 65. Bakar, F.A.; Yeo, C.C.; Harikrishna, J.A. Expression of the Streptococcus pneumoniae yoeB chromosomal toxin gene causes cell death in the model plant Arabidopsis thaliana. BMC Biotechnol. 2015, 15. 66. Brand, L.; Horler, M.; Nuesch, E.; Vassalli, S.; Barrell, P.; Yang, W.; Jefferson, R.A.; Grossniklaus, U.; Curtis, M.D. A versatile and reliable two-component system for tissue-specific gene induction in arabidopsis. Plant Physiol. 2006, 141, 1194–1204. 67. Borgen, B.H.; Thangstad, O.P.; Ahuja, I.; Rossiter, J.T.; Bones, A.M. Removing the mustard oil bomb from seeds: Transgenic ablation of myrosin cells in oilseed rape (Brassica napus) produces MINELESS seeds. J. Exp. Bot. 2010, 61, 1683–1697. 68. Nieto, C.; Cherny, I.; Khoo, S.K.; de Lacoba, M.G.; Chan, W.T.; Yeo, C.C.; Gazit, E.; Espinosa, M. The yefM-yoeB toxin-antitoxin systems of Escherichia coli and Streptococcus pneumoniae: Functional and structural correlation. J. Bacteriol. 2007, 189, 1266–1278. 69. Zuo, J.; Niu, Q.-W.; Chua, N.-H. An estrogen receptor-based transactivator XVE mediates highly inducible gene expression in transgenic plants. Plant J. 2000, 24, 265–273. 70. Slanchev, K.; Stebler, J.; de la Cueva-Méndez, G.; Raz, E. Development without germ cells: The role of the germ line in zebrafish sex differentiation. Proc. Natl. Acad. Sci. USA 2005, 102, 4074–4079. 71. Shimazu, T.; Degenhardt, K.; Nur-E-Kamal, A.; Zhang, J.; Yoshida, T.; Zhang, Y.; Mathew, R.; White, E.; Inouye, M. NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition. Genes Dev. 2007, 21, 929–941. 72. Browne, S.M.; Al-Rubeai, M. Selection methods for high-producing mammalian cell lines. Trends Biotechnol. 2007, 25, 425–432. 73. Nehlsen, K.; Herrmann, S.; Zauers, J.; Hauser, H.; Wirth, D. Toxin-antitoxin based transgene expression in mammalian cells. Nucleic Acids Res. 2010, 38. 74. Chono, H.; Matsumoto, K.; Tsuda, H.; Saito, N.; Lee, K.; Kim, S.; Shibata, H.; Ageyama, N.; Terao, K.; Yasutomi, Y.; et al. Acquisition of HIV-1 resistance in T lymphocytes using an ACA-specific E. coli mRNA interferase. Hum. Gene Ther. 2011, 22, 35–43. 75. Zhang, Y.; Zhang, J.; Hoeflich, K.P.; Ikura, M.; Qing, G.; Inouye, M. MazF cleaves cellular mRNAs specifically at ACA to block protein synthesis in Escherichia coli. Mol. Cell 2003, 12, 913–923. 76. Chono, H.; Saito, N.; Tsuda, H.; Shibata, H.; Ageyama, N.; Terao, K.; Yasutomi, Y.; Mineno, J.; Kato, I. In vivo safety and persistence of endoribonuclease gene-transduced CD4+ T cells in cynomolgus macaques for HIV-1 gene therapy model. PLoS ONE 2011, 6. 77. Park, J.-H.; Yamaguchi, Y.; Inouye, M. Intramolecular regulation of the sequence-specific mRNA interferase activity of MazF fused to a MazE fragment with a linker cleavable by specific proteases. Appl. Environ. Microbiol. 2012, 78, 3794–3799. 78. Shapira, A.; Shapira, S.; Gal-Tanamy, M.; Zemel, R.; Tur-Kaspa, R.; Benhar, I. Removal of hepatitis C virus-infected cells by a zymogenized bacterial toxin. PLoS ONE 2012, 7. 79. De la Cueva-Méndez, G. Systems and Methods for Diminishing Cell Growth and Inducing Selective Killing of Target Cells. WO2013037504 A4, 7 June 2013. 80. Preston, M.A.; Pimentel, B.; Bermejo-Rodríguez, C.; Dionne, I.; Turnbull, A.; de la Cueva-Méndez, G. Repurposing a prokaryotic toxin-antitoxin system for the selective killing of oncogenically stressed human cells. ACS Synth. Biol. 2015. 81. Bravo, A.; de Torrontegui, G.; Díaz, R. Identification of components of a new stability system of plasmid R1, ParD, that is close to the origin of replication of this plasmid. Mol. Gen. Genet. 1987, 210, 101–110. 82. Yamaguchi, Y.; Inouye, M. Type II toxin-antitoxin loci: The mazEF Family. In Prokaryotic Toxin-Antitoxins; Gerdes, K., Ed.; Springer-Verlag: Berlin, Germnay, 2013; pp. 107–136. 83. Wieteska, Ł.; Skulimowski, A.; Cybula, M.; Szemraj, J. Toxins vapC and pasB from prokaryotic TA modules remain active in mammalian cancer cells. Toxins 2014, 6, 2948–2961. 84. De la Cueva-Méndez, G.; Pimentel, B. Biotechnological and medical exploitation of toxin-antitoxin genes and their components. In Prokaryotic Toxin-Antitoxins; Gerdes, K., Ed.; Springer: Berlin, Germany, 2013; pp. 341–360. 85. Llosa, M.; Zupan, J.; Baron, C.; Zambryski, P. The N- and C-terminal portions of the agrobacterium VirB1 protein independently enhance tumorigenesis. J. Bacteriol. 2000, 182, 3437–3445. 86. Draper, O.; César, C.E.; Machón, C.; de la Cruz, F.; Llosa, M. Site-specific recombinase and integrase activities of a conjugative relaxase in recipient cells. Proc. Natl. Acad. Sci. USA 2005, 102, 16385–16390. 87. Llosa, M.; Roy, C.; Dehio, C. Bacterial type IV secretion systems in human disease. Mol. Microbiol. 2009, 73, 141–151. 88. González-Prieto, C.; Agúndez, L.; Linden, R.M.; Llosa, M. HUH site-specific recombinases for targeted modification of the human genome. Trends Biotechnol. 2013, 31, 305–312 89. Gerdes, K. Prokaryotic Toxin-Antitoxins, 1st ed.; Springer-Verlag: Berlin, Germany, 2013 |
| spellingShingle | Heterologous Expression of Toxins from Bacterial Toxin-Antitoxin Systems in Eukaryotic Cells: Strategies and Applications |
| subject | Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes one of which encodes a stable toxin and the other its cognate labile antitoxin. Certain environmental and physiological cues trigger the degradation of the antitoxin causing activation of the toxin leading either to the death or stasis of the host cell. TA systems have a variety of functions in the bacterial cell including acting as mediators of programmed cell death the induction of a dormant state known as persistence and the stable maintenance of plasmids and other mobile genetic elements. Some bacterial TA systems are functional when expressed in eukaryotic cells and this has led to several innovative applications which are the subject of this review. Here we look at how bacterial TA systems have been utilized for the genetic manipulation of yeasts and other eukaryotes for the containment of genetically modified organisms and for the engineering of high expression eukaryotic cell lines. We also examine how TA systems have been adopted as an important tool in developmental biology research for the ablation of specific cells and the potential for utility of TA systems in antiviral and anticancer gene therapies. |
| summary | Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes, one of which encodes a stable toxin and the other, its cognate labile antitoxin. Certain environmental and physiological cues trigger the degradation of the antitoxin, causing activation of the toxin, leading either to the death or stasis of the host cell. TA systems have a variety of functions in the bacterial cell, including acting as mediators of programmed cell death, the induction of a dormant state known as persistence and the stable maintenance of plasmids and other mobile genetic elements. Some bacterial TA systems are functional when expressed in eukaryotic cells and this has led to several innovative applications, which are the subject of this review. Here, we look at how bacterial TA systems have been utilized for the genetic manipulation of yeasts and other eukaryotes, for the containment of genetically modified organisms, and for the engineering of high expression eukaryotic cell lines. We also examine how TA systems have been adopted as an important tool in developmental biology research for the ablation of specific cells and the potential for utility of TA systems in antiviral and anticancer gene therapies. |
| title | Heterologous Expression of Toxins from Bacterial Toxin-Antitoxin Systems in Eukaryotic Cells: Strategies and Applications |
| title_full | Heterologous Expression of Toxins from Bacterial Toxin-Antitoxin Systems in Eukaryotic Cells: Strategies and Applications |
| title_fullStr | Heterologous Expression of Toxins from Bacterial Toxin-Antitoxin Systems in Eukaryotic Cells: Strategies and Applications |
| title_full_unstemmed | Heterologous Expression of Toxins from Bacterial Toxin-Antitoxin Systems in Eukaryotic Cells: Strategies and Applications |
| title_short | Heterologous Expression of Toxins from Bacterial Toxin-Antitoxin Systems in Eukaryotic Cells: Strategies and Applications |
| title_sort | heterologous expression of toxins from bacterial toxin-antitoxin systems in eukaryotic cells: strategies and applications |