EMBO Rep., published online 20 July 2012; doi:10.1038/embor.2012.106

During the stringent response, Escherichia coli use the alarmone ppGpp to rapidly respond to environmental changes. RelA, which makes ppGpp, is known to depend on the ribosomal protein L11 and to be activated by ribosomally bound deacylated tRNAPhe and mRNA, but it was not clear how these factors could explain a previous observation that production of ppGpp is nonlinear. Instead, Shyp et al. hypothesized that this amplification might be driven by the direct action of ppGpp on RelA. To test this idea, the authors added ppGpp to mixtures of RelA and 70S ribosomes at different time points, observing increased activity upon ppGpp addition. Activation was seen with concentrations of ppGpp that were consistent with availability of the molecule in the cell. Measurements of turnover rate with varying concentrations of ribosomes indicated that ppGpp increases product formation by affecting kcat, not Km. The effect of ppGpp is synergistic with that of other activators, with 10- to 20-fold activation of RelA observed with combinations of ribosomes, mRNA and deacylated tRNAPhe. The authors further show that L11 and ppGpp can serve as a minimal regulation system, though elevated concentrations of L11 were required for activation compared to regulation with intact ribsomes. This highly unusual mechanism of activation rather than inhibition by a reaction product provides a sensitive means by which cells can quickly sense and react to changes.