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Prokaryotic toxin–antitoxin stress response loci

Key Points

  • Prokaryotic toxin–antitoxin (TA) loci, such as relBE and mazEF, encode mRNA-cleaving enzymes that are activated by nutritional stress.

  • Slowly growing bacteria and Archaea have numerous TA loci. For example, Mycobacterium tuberculosis has 38 and Sulfolobus tokodaii has 32 TA loci.

  • Free-living bacteria have many TA loci whereas obligate intracellular organisms have none, consistent with a hypothesis that TA loci function as part of the cellular stress response.

  • RelE cleaves mRNA codons positioned at the ribosomal A-site, between the 2nd and 3rd nucleotide. RelE does not cleave naked mRNA in vitro if ribosomes aren't present.

  • Whereas mRNA cleavage by RelE is strictly dependent on the presence of ribosomes, MazF cleaves mRNAs site-specifically at ACA sites independently of the ribosomes. Whether the ribosomes have a role in MazF-mediated mRNA cleavage during physiological conditions is not resolved.

  • TA loci function as stress response elements that help the cells cope with nutritional stress, possibly by reducing the production of defective proteins during scarce conditions.

Abstract

Although toxin–antitoxin gene cassettes were first found in plasmids, recent database mining has shown that these loci are abundant in free-living prokaryotes, including many pathogenic bacteria. For example, Mycobacterium tuberculosis has 38 chromosomal toxin–antitoxin loci, including 3 relBE and 9 mazEF loci. RelE and MazF are toxins that cleave mRNA in response to nutritional stress. RelE cleaves mRNAs that are positioned at the ribosomal A-site, between the second and third nucleotides of the A-site codon. It has been proposed that toxin–antitoxin loci function in bacterial programmed cell death, but evidence now indicates that these loci provide a control mechanism that helps free-living prokaryotes cope with nutritional stress.

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Figure 1: Regulatory scheme showing connections in the stringent response pathway.
Figure 2: Genetic organization and components of toxin–antitoxin loci.
Figure 3: Distribution of toxin–antitoxin loci in prokaryotic chromosomes.
Figure 4: Model for relBE regulation and the delayed-relaxed response.

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Acknowledgements

We thank D. P. Pandey for technical help with database analyses. This work was supported by the Danish Biotechnology Instrument Center, The Carlsberg Foundation, The Danish Medical Research Council and an EC grant.

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Correspondence to Kenn Gerdes.

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DATABASES

Entrez

ccd

higBA

mazEF

parDE

phd/doc

relBE

ε

ζ

ω

SwissProt

CcdA

CcdB

Doc

HigA

HigB

MazE

MazF

Phd

RelB

RelE

FURTHER INFORMATION

Kenn Gerdes' homepage

Glossary

ALARMONES

Small molecules produced by bacteria that are exposed to internal or external stress such as starvation.

RelA

The enzyme, also known as ppGpp synthetase I, that synthesizes P4G in response to amino-acid starvation.

SpoT

This enzyme, also known as ppGpp synthetase II, has both P4G synthethase and hydrolase activities.

OPEN COMPLEX

For transcription the two strands of the DNA duplex must be unwound locally. An open complex is formed when RNA polymerase binds at a promoter and the duplex around the transcription start is unwound.

SECONDARY TUNNEL

A channel in the bacterial RNA polymerase, also known as the NTP uptake channel or the pore.

SIGMA (σ) FACTOR

The subunit of the RNA polymerase holoenzyme that is required for promoter sequence recognition and the ability to initiate transcription.

STRINGENT RESPONSE

The physiological changes that are elicited by amino-acid starvation.

INTEGRON

A genetic unit that, among others, encodes proteins that splice gene cassettes into chromosomes, where the cassettes can become functional.

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Gerdes, K., Christensen, S. & Løbner-Olesen, A. Prokaryotic toxin–antitoxin stress response loci. Nat Rev Microbiol 3, 371–382 (2005). https://doi.org/10.1038/nrmicro1147

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