MazG - A regulator of programmed cell death in Escherichia coli

We have previously reported that mazEF, the first regulatable chromosomal 'addiction module' located on the Escherichia coli chromosome, downstream from the relA gene, plays a crucial role in the programmed cell death in bacteria under stressful conditions. It consists of a pair of genes encoding a stable toxin, MazF, and MazE, a labile antitoxin interacting with MazF to form a complex. The cellular target of MazF toxin was recently described to be cellular mRNA, which is degraded by this toxin. On the same operon, downstream to the mazEF genes, we found another open reading frame, which was called mazG. Recently, it was shown that the MazG protein has a nucleotide pyrophosphohydrolase activity. Here we show that mazG is being transcribed in the same polycistronic mRNA with mazEF. We also show that the enzymatic activity of MazG is inhibited by MazEF proteins. When the complex MazEF was added, the enzymatic activity of MazG was about 70% inhibited. We demonstrate that the enzymatic activity of MazG in vivo causes depletion of guanosine 3′,5′-bispyrophosphate (ppGpp), synthesized by RelA under amino acid starvation conditions. Based on our results, we propose a model in which this third gene, which is unique for chromosomal addiction systems, has a function of limiting the deleterious activity of MazF toxin. In addition, MazG solves a frequently encountered biological problem: how to avoid the persistence of a toxic product beyond the time when its toxicity is useful to the survival of the population.