Abstract
Toxin–antitoxin (TA) systems, which consist of an intracellular toxin and its antidote (antitoxin), are encoded by ubiquitous genetic modules in prokaryotes. Commonly, the activity of a toxin is inhibited by its antitoxin under normal growth conditions. However, antitoxins are degraded in response to environmental stress, and toxins liberated from antitoxins consequently induce cell death or growth arrest. In free-living prokaryotes, TA systems are often present in large numbers and are considered to be associated with the adaptation of pathogenic bacteria or extremophiles to various unfavorable environments by shifting cells to a slow growth rate. Genomic analysis of the human pathogen Mycobacterium tuberculosis H37Rv (Mtb) revealed the presence of a large number of TA systems. Accordingly, we investigated five uncharacterized TA systems (Rv2019-Rv2018, Rv3697c-Rv3697A, Rv3180c-Rv3181c, Rv0299-Rv0298, and Rv3749c-Rv3750c) of Mtb. Among these, the expression of the Rv2019 toxin inhibited the growth of Escherichia coli, and M. smegmatis and this growth defect was recovered by the expression of the Rv2018 antitoxin. Interestingly, Rv3180c was toxic only in M. smegmatis, whose toxicity was neutralized by Rv3181c antitoxin. In vivo and in vitro assays revealed the ribosomal RNA (rRNA) cleavage activity of the Rv2019 toxin. Moreover, mRNAs appeared to be substrates of Rv2019. Therefore, we concluded that the ribonuclease activity of the Rv2019 toxin triggers the growth defect in E. coli and that the Rv2018 antitoxin inhibits the ribonuclease activity of the Rv2019 toxin.
Highlights
Toxin–antitoxin (TA) systems are encoded by ubiquitous genetic modules as an operon in prokaryotes and consist of an intracellular toxin and its antidote (Ramage et al, 2009)
The control of cell death system was first identified as a TA system in the Escherichia coli F plasmid (Jaffe et al, 1985); it is organized as an operon that contains two genes encoding a toxic protein (CcdB toxin) and an antidote protein (CcdA antitoxin)
We showed that expression of the Rv2019 toxin inhibited the growth of E. coli and that this growth defect was recovered by expression of the Rv2018 antitoxin
Summary
Toxin–antitoxin (TA) systems are encoded by ubiquitous genetic modules as an operon in prokaryotes and consist of an intracellular toxin and its antidote (antitoxin) (Ramage et al, 2009). These systems were known as plasmid addiction modules of large plasmids with low copy numbers (Van Melderen et al, 1994). The control of cell death (ccd) system was first identified as a TA system in the Escherichia coli F plasmid (Jaffe et al, 1985); it is organized as an operon that contains two genes encoding a toxic protein (CcdB toxin) and an antidote protein (CcdA antitoxin). Numerous TA systems have recently been discovered; these are encoded by prokaryotic genomes and are commonly considered stress-responsive genetic modules (Sevin and Barloy-Hubler, 2007; Shao et al, 2011)
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