ppGpp functions as an alarmone in metazoa

Guanosine 3,5 ' -bis(pyrophosphate) (ppGpp) functions as a second messenger in bacteria to adjust their physiology in response to environmental changes. In recent years, the ppGpp-specific hydrolase, metazoan SpoT homolog-1 (Mesh1), was shown to have important roles for growth under nutrient deficiency in Drosophila melanogaster. Curiously, however, ppGpp has never been detected in animal cells, and therefore the physiological relevance of this molecule, if any, in metazoans has not been established. Here, we report the detection of ppGpp in Drosophila and human cells and demonstrate that ppGpp accumulation induces metabolic changes, cell death, and eventually lethality in Drosophila. Our results provide the evidence of the existence and function of the ppGpp-dependent stringent response in animals. Ito et al. succeed in detecting guanosine tetraphosphate (ppGpp) in measurable levels in metazoan, specifically in Drosophila. They further demonstrate that the ppGpp-specific hydrolase, metazoan SpoT homolog-1 (Mesh1), is necessary, at least in certain conditions, to maintain low ppGpp levels, hence providing insights into the role of Mesh1 as a ppGpp hydrolase in vivo.