Regulation of growth and death in Escherichia coli by toxin–antitoxin systems

Key Points

  • The toxin–antitoxin (TA) systems of bacteria are new-comers in microbiology and biochemistry, as most of the discoveries about these systems have been made in the past decade. To date, it has been revealed that most bacteria and many archaea contain a number of highly diverse TA systems in their genomes.

  • In the type II TA systems, a toxin is constitutively co-expressed with its cognate antitoxin from a TA operon to form a stable complex in normally growing cells. As the antitoxin is less stable than the toxin in the cell, antitoxin has to be constantly produced to neutralize the cognate toxin. Under stress conditions, antitoxins are degraded by stress-induced proteases to release free toxins in the cells, resulting in cell growth arrest and eventual cell death.

  • Cellular targets of TA systems are highly diverse, from DNA replication to mRNA stability, protein synthesis, ATP production and cell wall biosynthesis. Other cellular targets are likely to be identified as more TA systems are discovered. The most frequent cellular targets for the Escherichia coli TA systems are mRNAs, perhaps because the inhibition of mRNA function seems to be the mildest means of regulating cell growth. Out of 36 TA systems in E. coli, 11 are known to interfere with mRNA.

  • As toxins targeting mRNA cleave cellular mRNAs, they are termed mRNA interferases. These mRNA interferases are grouped into two distinct classes depending on how they cleave mRNAs: ribosome-independent mRNA interferases and ribosome-dependent mRNA interferases (which cleave mRNAs at the ribosomal A site).

  • It has been shown that some toxins are induced under several stress conditions, including amino acid starvation, glucose starvation, DNA damage, heat and the addition of antibiotics; these toxins regulate cell growth, triggering programmed cell death. It is also predicted that the induction of some toxins is able to cause the persistent or quasi-dormant state, making these cells resistant to antibiotics. The toxins may also play a part in eliminating damaged cells from their populations.

  • Elucidation of the functions of these toxins is essential for our understanding of their roles in bacterial physiology under various stress conditions and also their roles in bacterial pathogenicity. The study of TA systems opens the door into a new and exciting field in medical research, molecular biology and biotechnology, as various toxins from TA systems may be used as new therapeutic tools. TA systems may also provide novel technologies for gene regulation and protein production.

Abstract

Escherichia coli K-12 contains at least 36 toxin genes, the expression of which causes growth inhibition and eventual death. These toxins are usually co-expressed with their cognate antitoxins in operons called toxin–antitoxin (TA) modules. Under normal growth conditions, toxins and antitoxins form stable complexes. However, stress-induced proteases preferentially eliminate unstable antitoxins, releasing free toxins to inhibit various cellular functions. TA systems have important roles in the physiology of cells in their natural habitats, including functions in biofilm formation and multidrug resistance. In this Review, we describe these TA systems in light of their functions and roles in the regulation of cell growth and death.

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Figure 1: Model for the regulation of toxin–antitoxin systems.
Figure 2: Genomic map of the toxin–antitoxin modules in Escherichia coli.
Figure 3: The crystal structures of toxin–antitoxin complexes.
Figure 4: The possible networks of toxin–antitoxin systems.
Figure 5: The multiple levels of autoregulation of the MazF–MazE toxin–antitoxin system.

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Acknowledgements

The authors are grateful to S. Phadtare and C. J. Mozdzierz for their critical reading of this article. This work was partially supported by a US National Institutes of Health grant (1RO1GM081567).

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Correspondence to Masayori Inouye.

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DATABASES

Protein Data Bank

1UB4

1WMI

Glossary

Antisense RNA

A complementary RNA sequence that binds to mRNA.

Autoinducer

A signalling molecule that causes the regulation of specific genes.

Outer-membrane vesicles

Enclosed compartments that are separated from the outer membrane in Gram-negative bacteria.

Fruiting body

A specialized spore-producing structure.

Stress-induced mutagenesis

The stress-induced reversible activation of error-prone DNA polymerases and downregulation of error-correcting enzymes, the result of which is an increased mutation rate in bacteria.

Stringent response

The physiological changes that are caused by amino acid starvation.

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Yamaguchi, Y., Inouye, M. Regulation of growth and death in Escherichia coli by toxin–antitoxin systems. Nat Rev Microbiol 9, 779–790 (2011). https://doi.org/10.1038/nrmicro2651

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