ppGpp functions as an alarmone in metazoa

Abstract

AbstractGuanosine 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 inDrosophila 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 inDrosophilaand human cells and demonstrate that ppGpp accumulation induces metabolic changes, cell death, and eventually lethality inDrosophila. Our results provide the evidence of the existence and function of the ppGpp-dependent stringent response in animals.