Journal of Biological Chemistry
Volume 290, Issue 9, 27 February 2015, Pages 5826-5839
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Microbiology
Cross-talk between Two Nucleotide-signaling Pathways in Staphylococcus aureus*

https://doi.org/10.1074/jbc.M114.598300Get rights and content
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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.

Background

Nucleotide-signaling pathways are complex systems that allow bacteria to rapidly respond to stress.

Results

Cyclic diadenosine monophosphate is essential for the growth of S. aureus, and its signaling network is intricately interconnected with the stringent response.

Conclusion

Cross-talk between different nucleotide-signaling networks is more common than previously anticipated.

Significance

Bacteria have evolved intricate signaling networks to survive.

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

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*

This work was supported by European Research Council Grant 260371 and Wellcome Trust Grant 100289 (to A. G.).

This article contains supplemental Table S1.

1

Supported by a Medical Research Council Centre for Molecular Bacteriology and Infection (MRC CMBI) studentship.