title: Cross-talk between two nucleotide-signaling pathways in Staphylococcus aureus.
abstract: Nucleotide-signaling pathways are found in all kingdoms of life and are utilized to coordinate a rapid response to external stimuli. The stringent response alarmones guanosine tetra- (ppGpp) and pentaphosphate (pppGpp) control a global response allowing cells to adapt to starvation conditions such as amino acid depletion. One more recently discovered signaling nucleotide is the secondary messenger cyclic diadenosine monophosphate (c-di-AMP). Here, we demonstrate that this signaling nucleotide is essential for the growth of Staphylococcus aureus, and its increased production during late growth phases indicates that c-di-AMP controls processes that are important for the survival of cells in stationary phase. By examining the transcriptional profile of cells with high levels of c-di-AMP, we reveal a significant overlap with a stringent response transcription signature. Examination of the intracellular nucleotide levels under stress conditions provides further evidence that high levels of c-di-AMP lead to an activation of the stringent response through a RelA/SpoT homologue (RSH) enzyme-dependent increase in the (p)ppGpp levels. This activation is shown to be indirect as c-di-AMP does not interact directly with the RSH protein. Our data extend this interconnection further by showing that the S. aureus c-di-AMP phosphodiesterase enzyme GdpP is inhibited in a dose-dependent manner by ppGpp, which itself is not a substrate for this enzyme. Altogether, these findings add a new layer of complexity to our understanding of nucleotide signaling in bacteria as they highlight intricate interconnections between different nucleotide-signaling networks.
authors.affiliation: From the Section of Microbiology and Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, United Kingdom and.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Corrigan
authors.affiliation: From the Section of Microbiology and Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, United Kingdom and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bowman
authors.affiliation: From the Section of Microbiology and Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, United Kingdom and.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Willis
authors.affiliation: the Research Core Unit Metabolomics, Hannover Medical School, Hannover D-306625, Germany.
authors.forename: Volkhard
authors.initials: V
authors.lastname: Kaever
authors.affiliation: From the Section of Microbiology and Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, United Kingdom and a.grundling@imperial.ac.uk.
authors.forename: Angelika
authors.initials: A
authors.lastname: Gründling
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002455:Cell Division / Q000235:genetics; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D006158:Guanosine Pentaphosphate / Q000378:metabolism*; D006159:Guanosine Tetraphosphate / Q000378:metabolism*; D050296:Microbial Viability / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D015226:Dinucleoside Phosphates; D006159:Guanosine Tetraphosphate; D006158:Guanosine Pentaphosphate
keywords: Bacterial Signal Transduction; Cyclic Nucleotide; Gene Regulation; Microarray; Phosphodiesterases; Stress Response; staphylococcus aureus (S. aureus)