Rapid curtailing of the stringent response by toxin-antitoxin module-encoded mRNases

Chengzhe Tian, Mohammed Roghanian, Mikkel Girke Jørgensen, Kim Sneppen, Michael Askvad Sørensen, Kenn Gerdes, Namiko Mitarai

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Escherichia coli regulates its metabolism to adapt to changes in the environment, in particular to stressful downshifts in nutrient quality. Such shifts elicit the so-called stringent response, coordinated by the alarmone guanosine tetra- and pentaphosphate [(p)ppGpp]. On sudden amino acid (aa) starvation, RelA [(p)ppGpp synthetase I] activity is stimulated by binding of uncharged tRNAs to a vacant ribosomal site; the (p)ppGpp level increases dramatically and peaks within the time scale of a few minutes. The decrease of the (p)ppGpp level after the peak is mediated by the decreased production of mRNA by (p)ppGpp-associated transcriptional regulation, which reduces the vacant ribosomal A site and thus constitutes negative feedback to the RelA-dependent (p)ppGpp synthesis. Here we showed that on sudden isoleucine starvation, this peak was higher in an E. coli strain that lacks the 10 known mRNase-encoding toxin-antitoxin (TA) modules present in the wild-type (wt) strain. This observation suggested that toxins are part of the negative-feedback mechanism to control the (p)ppGpp level during the early stringent response. We built a ribosome trafficking model to evaluate the fold increase in RelA activity just after the onset of aa starvation. Combining this with a feedback model between the (p)ppGpp level and the mRNA level, we obtained reasonable fits to the experimental data for both strains. The analysis revealed that toxins are activated rapidly, within a minute after the onset of starvation, reducing the mRNA half-life by~30%.

Original languageEnglish
JournalJournal of Bacteriology
Issue number14
Pages (from-to)1918-1926
Publication statusPublished - 27. Jun 2016


  • Antitoxins/genetics
  • Bacterial Toxins/genetics
  • Escherichia coli Proteins/genetics
  • Escherichia coli/enzymology
  • Gene Expression Regulation, Bacterial
  • Guanosine Tetraphosphate/metabolism
  • RNA, Messenger/genetics
  • RNA, Transfer/genetics
  • Ribonucleases/genetics


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