Abstract
Nucleotide signaling networks are key to facilitate alterations in gene expression, protein function, and enzyme activity in response to diverse stimuli. Cyclic di-adenosine monophosphate (c-di-AMP) is an important secondary messenger molecule produced by the human pathogen Staphylococcus aureus and is involved in regulating a number of physiological processes including potassium transport. S. aureus must ensure tight control over its cellular levels as both high levels of the dinucleotide and its absence result in a number of detrimental phenotypes. Here we show that in addition to the membrane-bound Asp-His-His and Asp-His-His-associated (DHH/DHHA1) domain-containing phosphodiesterase (PDE) GdpP, S. aureus produces a second cytoplasmic DHH/DHHA1 PDE Pde2. Although capable of hydrolyzing c-di-AMP, Pde2 preferentially converts linear 5′-phosphadenylyl-adenosine (pApA) to AMP. Using a pde2 mutant strain, pApA was detected for the first time in S. aureus, leading us to speculate that this dinucleotide may have a regulatory role under certain conditions. Moreover, pApA is involved in a feedback inhibition loop that limits GdpP-dependent c-di-AMP hydrolysis. Another protein linked to the regulation of c-di-AMP levels in bacteria is the predicted regulator protein YbbR. Here, it is shown that a ybbR mutant S. aureus strain has increased acid sensitivity that can be bypassed by the acquisition of mutations in a number of genes, including the gene coding for the diadenylate cyclase DacA. We further show that c-di-AMP levels are slightly elevated in the ybbR suppressor strains tested as compared with the wild-type strain. With this, we not only identified a new role for YbbR in acid stress resistance in S. aureus but also provide further insight into how c-di-AMP levels impact acid tolerance in this organism.
Highlights
The Gram-positive bacterium Staphylococcus aureus is persistently carried by ϳ30% of the human population [1]
The signaling molecule c-di-AMP is predominantly produced by Gram-positive bacteria belonging to the Firmicutes and Actinobacteria phyla but can be synthesized by some Gram-negative bacteria [7,8,9,10,11,12,13,14]. c-di-AMP is synthesized from two molecules of ATP via a condensation reaction requiring the activity of a diadenylate cyclase (DAC), and hydrolyzed by a phosphodiesterase (PDE) into 5Ј-phosphadenylyl-adenosine, or two molecules of AMP [7, 8, 10, 15,16,17]
GdpP homologs have since been discovered in a range of microorganisms including Streptococcus pneumoniae, Listeria monocytogenes and S. aureus, and function to degrade c-di-AMP into phosphodiesterase (PDE) into 5Ј-phosphadenylyl-adenosine (pApA) [7, 17, 24, 25]
Summary
Nucleotide signaling networks are key to facilitate alterations in gene expression, protein function, and enzyme activity in response to diverse stimuli. Cyclic di-adenosine monophosphate (c-di-AMP) is an important secondary messenger molecule produced by the human pathogen Staphylococcus aureus and is involved in regulating a number of physiological processes including potassium transport. The functions of the stringent response alarmones guanosine tetraphosphate and pentaphosphate ((p)ppGpp) have been extensively investigated These nucleotides are produced under various stress conditions including nutrient limitation. GdpP homologs have since been discovered in a range of microorganisms including Streptococcus pneumoniae, Listeria monocytogenes and S. aureus, and function to degrade c-di-AMP into pApA [7, 17, 24, 25]. In this study we further investigated the c-di-AMP metabolism in S. aureus by examining the function of the DHH/ DHHA1 PDE Pde and the membrane protein YbbR. Its absence leads to increased acid sensitivity, which can be compensated by the production of an altered DacA variant
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