Novel biological functions of ppGpp in Escherichia coli

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The signaling molecule (p)ppGpp (guanosine pentaphosphate or tetraphosphate) is a widespread bacterial second messenger. It is best known as alarmone that alerts the cell to starvation conditions and leads to major re-arrangements in bacterial physiology. In Escherichia coli, the accumulation of (p)ppGpp inhibits transcription of ribosomal genes and promotes transcription of genes for biosynthetic pathways. We found that (p)ppGpp affects the growth-rate controlled proteolysis of at least two substrates of the FtsH protease. The substrate LpxC is essential for lipopolysaccharide (LPS) biosynthesis and YfgM is a membrane protein involved in signaling of stress conditions.The first aim of this proposal is to determine whether degradation of other proteins is also affected by (p)ppGpp. Among the candidates to be tested will be known and novel clients of the FtsH and Lon proteases. Next, we will address how proteolysis is coordinated by the absence or presence of (p)ppGpp. We will clarify whether (p)ppGpp acts directly by binding to either the protease or the substrate or whether it acts indirectly by protein factors. Finally, we plan to establish a capture protocol to enrich (p)ppGpp-binding proteins and RNAs in E. coli. We expect to provide new insights into the role of (p)ppGpp in proteolytic processes in particular and into the central position of the second messenger in bacterial physiology in general.