Cyclic Di-AMP Impairs Potassium Uptake Mediated by a Cyclic Di-AMP Binding Protein in Streptococcus pneumoniae

Bai, Yang; Yang, Jun; Zarrella, Tiffany M.; Zhang, Yang; Metzger, Dennis W.; Bai, Guangchun

doi:10.1128/jb.01041-13

Cited by 131 publications

(184 citation statements)

References 52 publications

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“…The presence of membrane bound and intracellular gating components has been suggested for the TrkAH systems in Halomonas elongata (56), Vibrio alginolyticus (57), and Vibrio parahaemolyticus (58). Proteins similar to Trk proteins have also been shown to function in response to interaction with physiological messengers such as cyclic di-AMP (c-di-AMP) (59,60). Trk2 in S. mutans has two components, which include a membrane-bound TrkH component, which presumably allows the transfer of cations through the cell membrane, and a TrkA component, which likely controls the movement of K ϩ into the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Trk2 Potassium Transport System in Streptococcus mutans and Its Role in Potassium Homeostasis, Biofilm Formation, and Stress Tolerance

et al. 2016

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Potassium (K؉ ) is the most abundant cation in the fluids of dental biofilm. The biochemical and biophysical functions of K ؉ and a variety of K ؉ transport systems have been studied for most pathogenic bacteria but not for oral pathogens. In this study, we establish the modes of K ؉ acquisition in Streptococcus mutans and the importance of K ؉ homeostasis for its virulence attributes. The S. mutans genome harbors four putative K ؉ transport systems that included two Trk-like transporters (designated Trk1 and Trk2), one glutamate/K ؉ cotransporter (GlnQHMP), and a channel-like K ؉ transport system (Kch). Mutants lacking Trk2 had significantly impaired growth, acidogenicity, aciduricity, and biofilm formation. [K ؉ ] less than 5 mM eliminated biofilm formation in S. mutans. The functionality of the Trk2 system was confirmed by complementing an Escherichia coli TK2420 mutant strain, which resulted in significant K ؉ accumulation, improved growth, and survival under stress. Taken together, these results suggest that Trk2 is the main facet of the K ؉ -dependent cellular response of S. mutans to environment stresses. IMPORTANCEBiofilm formation and stress tolerance are important virulence properties of caries-causing Streptococcus mutans. To limit these properties of this bacterium, it is imperative to understand its survival mechanisms. Potassium is the most abundant cation in dental plaque, the natural environment of S. mutans. K ؉ is known to function in stress tolerance, and bacteria have specialized mechanisms for its uptake. However, there are no reports to identify or characterize specific K ؉ transporters in S. mutans. We identified the most important system for K ؉ homeostasis and its role in the biofilm formation, stress tolerance, and growth. We also show the requirement of environmental K ؉ for the activity of biofilm-forming enzymes, which explains why such high levels of K ؉ would favor biofilm formation. Bacteria utilize specialized endogenous mechanisms to survive and proliferate in transient environments. A common bacterial response to environmental perturbations, such as acid stress, osmotic tension, and nutrient deprivation, is to accumulate certain solutes, such as potassium (K ϩ ). K ϩ , a naturally abundant cation, is present in all types of cells and is essential for both cell survival and physiology. K ϩ accumulation under stress conditions enables organisms to contend with dehydration, membrane damage, regulation of the Na ϩ /H ϩ -dependent cell energetics, and pH homeostasis while simultaneously minimizing interference with the structures and functions of intracellular proteins (1-3).In prokaryotes, four main K ϩ transport systems have been identified, which include the proteins Trk (or Ktr), Kdp, Kup, and channel-like Kch (4), all of which have different K ϩ affinities. Their variety and independent functioning have likely evolved as a cell survival strategy to ensure that adequate levels of K ϩ are present at all times to contend with environmental changes (5). These systems are r...

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Section: Discussionmentioning

confidence: 99%

Trk2 Potassium Transport System in Streptococcus mutans and Its Role in Potassium Homeostasis, Biofilm Formation, and Stress Tolerance

et al. 2016

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“…Several global regulatory pathways that link metabolic stress to guanine metabolism have been identified, including (p)ppGpp and the stringent response (37) and the transcription regulator CodY (58). Other mutants represent pathways that link other aspects of nucleotide metabolism to general stress responses, including the second messenger cyclic-di-AMP phosphodiesterase GdpP (55,59,60), which has recently been linked to potassium import under osmotic stress (61)(62)(63). If triggering a stress response is a characteristic shared by other mutations in this collection, then it is possible that those involving the loss of function of a single subunit of a multicomponent membrane transporter may cause a membrane perturbation that induces a stress response.…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pyogenes Polymyxin B-Resistant Mutants Display Enhanced ExPortal Integrity

et al. 2014

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The ExPortal protein secretion organelle in Streptococcus pyogenes is an anionic phospholipid-containing membrane microdomain enriched in Sec translocons and postsecretion protein biogenesis factors. Polymyxin B binds to and disrupts ExPortal integrity, resulting in defective secretion of several toxins. To gain insight into factors that influence ExPortal organization, a genetic screen was conducted to select for spontaneous polymyxin B-resistant mutants displaying enhanced ExPortal integrity. Whole-genome resequencing of 25 resistant mutants revealed from one to four mutations per mutant genome clustered primarily within a core set of 10 gene groups. Construction of mutants with individual deletions or insertions demonstrated that 7 core genes confer resistance and enhanced ExPortal integrity through loss of function, while 3 were likely due to gain of function and/or combinatorial effects. Core resistance genes include a transcriptional regulator of lipid biosynthesis, several genes involved in nutrient acquisition, and a variety of genes involved in stress responses. Two members of the latter class also function as novel regulators of the secreted SpeB cysteine protease. Analysis of the most frequently isolated mutation, a single nucleotide deletion in a track of 9 consecutive adenine residues in pstS, encoding a component of a high-affinity P i transporter, suggests that this sequence functions as a molecular switch to facilitate stress adaptation. Together, these data suggest the existence of a membrane stress response that promotes enhanced ExPortal integrity and resistance to cationic antimicrobial peptides.

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“…In several Gram-positive bacteria, c-di-AMP binds and inhibits KtrA, the cytoplasmic gating component of the KtrAB potassium transporter (17,19). Moreover, c-di-AMP also binds the ydaO riboswitch, which is located upstream of the ktrAB operon and controls its expression (23).…”

mentioning

confidence: 99%

“…CdaA is the most widespread diadenylate cyclase, and it is the only such enzyme in pathogenic firmicutes. CdaA has been implicated in the control of cell wall and potassium homeostasis (6,(16)(17)(18)(19). The cdaA gene is the first gene of a widely conserved gene cluster that also encodes a regulatory protein, CdaR, and enzymes that generate glucosamine-1- …”

mentioning

confidence: 99%

An Essential Poison: Synthesis and Degradation of Cyclic Di-AMP in Bacillus subtilis

et al. 2015

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Gram-positive bacteria synthesize the second messenger cyclic di-AMP (c-di-AMP) to control cell wall and potassium homeostasis and to secure the integrity of their DNA. In the firmicutes, c-di-AMP is essential for growth. The model organism Bacillus subtilis encodes three diadenylate cyclases and two potential phosphodiesterases to produce and degrade c-di-AMP, respectively. Among the three cyclases, CdaA is conserved in nearly all firmicutes, and this enzyme seems to be responsible for the c-di-AMP that is required for cell wall homeostasis. Here, we demonstrate that CdaA localizes to the membrane and forms a complex with the regulatory protein CdaR and the glucosamine-6-phosphate mutase GlmM. Interestingly, cdaA, cdaR, and glmM form a gene cluster that is conserved throughout the firmicutes. This conserved arrangement and the observed interaction between the three proteins suggest a functional relationship. Our data suggest that GlmM and GlmS are involved in the control of c-di-AMP synthesis. These enzymes convert glutamine and fructose-6-phosphate to glutamate and glucosamine-1-phosphate. c-di-AMP synthesis is enhanced if the cells are grown in the presence of glutamate compared to that in glutamine-grown cells. Thus, the quality of the nitrogen source is an important signal for c-di-AMP production. In the analysis of c-di-AMP-degrading phosphodiesterases, we observed that both phosphodiesterases, GdpP and PgpH (previously known as YqfF), contribute to the degradation of the second messenger. Accumulation of c-di-AMP in a gdpP pgpH double mutant is toxic for the cells, and the cells respond to this accumulation by inactivation of the diadenylate cyclase CdaA. IMPORTANCEBacteria use second messengers for signal transduction. Cyclic di-AMP (c-di-AMP) is the only second messenger known so far that is essential for a large group of bacteria. We have studied the regulation of c-di-AMP synthesis and the role of the phosphodiesterases that degrade this second messenger. c-di-AMP synthesis strongly depends on the nitrogen source: glutamategrown cells produce more c-di-AMP than glutamine-grown cells. The accumulation of c-di-AMP in a strain lacking both phosphodiesterases is toxic and results in inactivation of the diadenylate cyclase CdaA. Our results suggest that CdaA is the critical diadenylate cyclase that produces the c-di-AMP that is both essential and toxic upon accumulation. In order to process environmental information in the cell, many organisms are capable of synthesizing so-called second messengers. These small molecules are formed in response to primary signals and perceived by cellular targets. Bacteria often use specific nucleotides as second messengers. These nucleotides include cyclic mononucleotides, such as cyclic AMP (cAMP) and cyclic GMP (cGMP), as well as cyclic dinucleotides, such as cyclic di-AMP (c-di-AMP), cyclic di-GMP (c-di-GMP), and (p) ppGpp (1-3).The investigation of c-di-AMP-mediated signaling has recently attracted much attention (2). This molecule is formed by many bacteria a...

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Cyclic Di-AMP Impairs Potassium Uptake Mediated by a Cyclic Di-AMP Binding Protein in Streptococcus pneumoniae

Cited by 131 publications

References 52 publications

Trk2 Potassium Transport System in Streptococcus mutans and Its Role in Potassium Homeostasis, Biofilm Formation, and Stress Tolerance

Trk2 Potassium Transport System in Streptococcus mutans and Its Role in Potassium Homeostasis, Biofilm Formation, and Stress Tolerance

Streptococcus pyogenes Polymyxin B-Resistant Mutants Display Enhanced ExPortal Integrity

An Essential Poison: Synthesis and Degradation of Cyclic Di-AMP in Bacillus subtilis

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