Cross-talk between two nucleotide-signaling pathways in Staphylococcus aureus

J Biol Chem. 2015 Feb 27;290(9):5826-39. doi: 10.1074/jbc.M114.598300. Epub 2015 Jan 9.


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.

Keywords: Bacterial Signal Transduction; Cyclic Nucleotide; Gene Regulation; Microarray; Phosphodiesterases; Stress Response; staphylococcus aureus (S. aureus).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Blotting, Western
  • Cell Division / genetics
  • Dinucleoside Phosphates / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Bacterial
  • Guanosine Pentaphosphate / metabolism*
  • Guanosine Tetraphosphate / metabolism*
  • Microbial Viability / genetics
  • Oligonucleotide Array Sequence Analysis
  • Signal Transduction*
  • Staphylococcus aureus / genetics
  • Staphylococcus aureus / growth & development
  • Staphylococcus aureus / metabolism*


  • Bacterial Proteins
  • Dinucleoside Phosphates
  • Guanosine Tetraphosphate
  • Guanosine Pentaphosphate