VapBC

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Crystallographic tertiary structure of a VapC toxin PIN domain.

VapBC (virulence associated proteins B and C) is the largest family of type II toxin-antitoxin system genetic loci in prokaryotes.[1] VapBC operons consist of two genes: VapC encodes a toxic PilT N-terminus (PIN) domain, and VapB encodes a matching antitoxin.[2] The toxins in this family are thought to perform RNA cleavage, which is inhibited by the co-expression of the antitoxin, in a manner analogous to a poison and antidote.

First discovered in 1992, vapBC loci are now thought make up around 37–42% of all type II toxin-antitoxin systems.[3][4]

Discovery

Following the discoveries of two other type II toxin-antitoxin systems,[5][6] the first vapBC system to be characterised was found in Salmonella dublin strain G19 in 1992.[7] It was characterised as a system for ensuring that all daughter cells contained a copy of the plasmid encoding the vapBC locus. The two components of this plasmidic system were originally named vagC and vagD (virulence-associated gene) for the toxin and antitoxin genes respectively. VagC was predicted to encode a 12kDa polypeptide, while vagD encoded a smaller 10kDa protein.[7] Their open reading frames were found to overlap by a single nucleotide; suggesting they were translated together, and at a constant molar ratio.[8]

Distribution

VapBC operons have been found in distantly related prokaryotes, including the pathogens Leptospira interrogans,[9] Mycobacterium tuberculosis[10] and Piscirickettsia salmonis.[11] The loci have been described as "surprisingly abundant, especially in Archaea"[12]—vapBC family members made up 37% of all TA families identified by one bioinformatics search[3] and 42% of those found by another.[4]

Bioinformatics searches have discovered vapBC homologues on both chromosomes and plasmids, and often in high copy number per cell. They are less common, however, in firmicutes and cyanobacteria.[3] Genomes with high numbers of vapBC loci include: M. tuberculosis with 45 predicted loci;[10] S.tokodaii with 25;[4] S.solfataricus with 23[4] and Sinorhizobium meliloti with 21.[10]

Function(s)

VapC toxins, specifically the PIN domains, act as ribonucleases in cleaving RNA molecules, thereby reducing the rate of translation.[10][13] In the bacteria Shigella flexneri and Salmonella enterica, VapC toxins have been shown to perform specific cleavage of a tRNA, but in other bacteria the RNA cleavage may be less specific.[14]

VapC is strongly inhibited by direct protein interaction with VapB, its cognate antitoxin. The toxin-antitoxin complex is thought to autoregulate its own operon, repressing transcription of both components through a DNA-binding domain in VapB.[15]

In some organisms, vapBC loci have been assigned other potential functions. In the hyperthermophilic archaean Sulfolobus solfataricus, for example, a vapBC gene cassette is though to regulate heat shock response.[2]

See also

References

  1. ↑ Robson, Jennifer; McKenzie, Joanna L., Cursons, Ray, Cook, Gregory M., Arcus, Vickery L. (17 July 2009). "The vapBC Operon from Mycobacterium smegmatis Is An Autoregulated Toxin–Antitoxin Module That Controls Growth via Inhibition of Translation". Journal of Molecular Biology 390 (3): 353–367. doi:10.1016/j.jmb.2009.05.006. PMID 19445953. 
  2. ↑ 2.0 2.1 Cooper, CR; Daugherty, AJ, Tachdjian, S, Blum, PH, Kelly, RM (2009 Feb). "Role of vapBC toxin-antitoxin loci in the thermal stress response of Sulfolobus solfataricus". Biochemical Society transactions 37 (Pt 1): 123–6. doi:10.1042/BST0370123. PMC 2919284. PMID 19143615. Retrieved 11 May 2011. 
  3. ↑ 3.0 3.1 3.2 Sevin, Emeric W; Barloy-Hubler, Frédérique (1 January 2007). "RASTA-Bacteria: a web-based tool for identifying toxin-antitoxin loci in prokaryotes". Genome Biology 8 (8): R155. doi:10.1186/gb-2007-8-8-r155. PMC 2374986. PMID 17678530. Retrieved 11 May 2011. 
  4. ↑ 4.0 4.1 4.2 4.3 Pandey, D. P.; Gerdes, K (18 February 2005). "Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes". Nucleic Acids Research 33 (3): 966–976. doi:10.1093/nar/gki201. PMC 549392. PMID 15718296. Retrieved 13 May 2011. 
  5. ↑ Ogura, T; Hiraga, S (1983 Aug). "Mini-F plasmid genes that couple host cell division to plasmid proliferation". Proceedings of the National Academy of Sciences of the United States of America 80 (15): 4784–8. doi:10.1073/pnas.80.15.4784. PMC 384129. PMID 6308648. Retrieved 13 May 2011. 
  6. ↑ Bravo, A; de Torrontegui, G, Díaz, R (1987 Nov). "Identification of components of a new stability system of plasmid R1, ParD, that is close to the origin of replication of this plasmid". Molecular & general genetics : MGG 210 (1): 101–10. PMID 3323833. 
  7. ↑ 7.0 7.1 Pullinger, GD; Lax, AJ (1992 Jun). "A Salmonella dublin virulence plasmid locus that affects bacterial growth under nutrient-limited conditions". Molecular microbiology 6 (12): 1631–43. doi:10.1111/j.1365-2958.1992.tb00888.x. PMID 1495391. 
  8. ↑ Das, A; Yanofsky, C (1989-11-25). "Restoration of a translational stop-start overlap reinstates translational coupling in a mutant trpB'-trpA gene pair of the Escherichia coli tryptophan operon". Nucleic Acids Research 17 (22): 9333–40. doi:10.1093/nar/17.22.9333. PMC 335135. PMID 2685759. Retrieved 13 May 2011. 
  9. ↑ Zhang, YX; Li, J, Guo, XK, Wu, C, Bi, B, Ren, SX, Wu, CF, Zhao, GP (2004 Jun). "Characterization of a novel toxin-antitoxin module, VapBC, encoded by Leptospira interrogans chromosome". Cell research 14 (3): 208–16. doi:10.1038/sj.cr.7290221. PMID 15225414. 
  10. ↑ 10.0 10.1 10.2 10.3 Arcus, V. L.; McKenzie, J. L., Robson, J., Cook, G. M. (29 October 2010). "The PIN-domain ribonucleases and the prokaryotic VapBC toxin-antitoxin array". Protein Engineering Design and Selection 24 (1–2): 33–40. doi:10.1093/protein/gzq081. PMID 21036780. 
  11. ↑ Gómez, FA; Cárdenas, C, Henríquez, V, Marshall, SH (2011 Apr). "Characterization of a functional toxin-antitoxin module in the genome of the fish pathogen Piscirickettsia salmonis". FEMS microbiology letters 317 (1): 83–92. doi:10.1111/j.1574-6968.2011.02218.x. PMID 21241361. 
  12. ↑ Gerdes, K; Christensen, SK, Løbner-Olesen, A (2005 May). "Prokaryotic toxin-antitoxin stress response loci". Nature reviews. Microbiology 3 (5): 371–82. doi:10.1038/nrmicro1147. PMID 15864262. 
  13. ↑ Van Melderen, Laurence (1 December 2010). "Toxin–antitoxin systems: why so many, what for?". Current Opinion in Microbiology 13 (6): 781–785. doi:10.1016/j.mib.2010.10.006. PMID 21041110. 
  14. ↑ Winther, K. S.; Gerdes, K. (18 April 2011). "Enteric virulence associated protein VapC inhibits translation by cleavage of initiator tRNA". Proceedings of the National Academy of Sciences 108 (18): 7403–7407. doi:10.1073/pnas.1019587108. 
  15. ↑ Miallau, L.; Faller, M., Chiang, J., Arbing, M., Guo, F., Cascio, D., Eisenberg, D. (4 November 2008). "Structure and Proposed Activity of a Member of the VapBC Family of Toxin-Antitoxin Systems: VapBC-5 from Mycobacterium tuberculosis". Journal of Biological Chemistry 284 (1): 276–283. doi:10.1074/jbc.M805061200. PMC 2610494. PMID 18952600. Retrieved 13 May 2011. 

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