Concentration matters!! ppGpp, from a whispering to a strident alarmone.

Bacteria have developed sophisticated signal transduction pathways to sense and respond to environmental stresses. These pathways include intracellular regulators that elicit adaptive changes in the physiology of the cell. Extensive work, mostly performed in Escherichia coli, showed that the modified nucleotide ppGpp plays a key regulatory role by co-ordinating the cellular responses to adverse environmental conditions. In this issue of Molecular Microbiology, Traxler et al. define two sets of ppGpp-dependent genes that are expressed at different times after induction of ppGpp synthesis. Their results suggest that quantitative differences in the ppGpp intracellular concentration determine the precise pattern of gene expression during adaptation process: low levels of ppGpp suffice to activate the Lrp regulon, which, by activating the synthesis of some amino acid pathways, can generate a negative feedback loop while high levels activate RpoS and a feed-forward amplification of the general stress response. These dose-dependent effects on gene expression open new perspectives on the complex regulatory pathways mediated by ppGpp during environmental adaptation.