Dataset Information

Making and Breaking of an Essential Poison: the Cyclases and Phosphodiesterases That Produce and Degrade the Essential Second Messenger Cyclic di-AMP in Bacteria.

ABSTRACT: Cyclic di-AMP is a second-messenger nucleotide that is produced by many bacteria and some archaea. Recent work has shown that c-di-AMP is unique among the signaling nucleotides, as this molecule is in many bacteria both essential on one hand and toxic upon accumulation on the other. Moreover, in bacteria, like Bacillus subtilis, c-di-AMP controls a biological process, potassium homeostasis, by binding both potassium transporters and riboswitch molecules in the mRNAs that encode the potassium transporters. In addition to the control of potassium homeostasis, c-di-AMP has been implicated in many cellular activities, including DNA repair, cell wall homeostasis, osmotic adaptation, biofilm formation, central metabolism, and virulence. c-di-AMP is synthesized and degraded by diadenylate cyclases and phosphodiesterases, respectively. In the diadenylate cyclases, one type of catalytic domain, the diadenylate cyclase (DAC) domain, is coupled to various other domains that control the localization, the protein-protein interactions, and the regulation of the enzymes. The phosphodiesterases have a catalytic core that consists either of a DHH/DHHA1 or of an HD domain. Recent findings on the occurrence, domain organization, activity control, and structural features of diadenylate cyclases and phosphodiesterases are discussed in this review.

SUBMITTER: Commichau FM

PROVIDER: S-EPMC6287462 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Making and Breaking of an Essential Poison: the Cyclases and Phosphodiesterases That Produce and Degrade the Essential Second Messenger Cyclic di-AMP in Bacteria.

Commichau Fabian M FM Heidemann Jana L JL Ficner Ralf R Stülke Jörg J

Journal of bacteriology 20181207 1

Cyclic di-AMP is a second-messenger nucleotide that is produced by many bacteria and some archaea. Recent work has shown that c-di-AMP is unique among the signaling nucleotides, as this molecule is in many bacteria both essential on one hand and toxic upon accumulation on the other. Moreover, in bacteria, like <i>Bacillus subtilis</i>, c-di-AMP controls a biological process, potassium homeostasis, by binding both potassium transporters and riboswitch molecules in the mRNAs that encode the potass ...[more]

PMID: 30224435

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Project description:Streptococcus pneumoniae (the pneumococcus) is a naturally competent organism that causes diseases such as pneumonia, otitis media, and bacteremia. The essential bacterial second messenger cyclic di-AMP (c-di-AMP) is an emerging player in the stress responses of many pathogens. In S. pneumoniae, c-di-AMP is produced by a diadenylate cyclase, CdaA, and cleaved by phosphodiesterases Pde1 and Pde2. c-di-AMP binds a transporter of K+ (Trk) family protein, CabP, which subsequently halts K+ uptake via the transporter TrkH. Recently, it was reported that Pde1 and Pde2 are essential for pneumococcal virulence in mouse models of disease. To elucidate c-di-AMP-mediated transcription that may lead to changes in pathogenesis, we compared the transcriptomes of wild-type (WT) and Δpde1 Δpde2 strains by transcriptome sequencing (RNA-Seq) analysis. Notably, we found that many competence-associated genes are significantly upregulated in the Δpde1 Δpde2 strain compared to the WT. These genes play a role in DNA uptake, recombination, and autolysis. Competence is induced by a quorum-sensing mechanism initiated by the secreted factor competence-stimulating peptide (CSP). Surprisingly, the Δpde1 Δpde2 strain exhibited reduced transformation efficiency compared to WT bacteria, which was c-di-AMP dependent. Transformation efficiency was also directly related to the [K+] in the medium, suggesting a link between c-di-AMP function and the pneumococcal competence state. We found that a strain that possesses a V76G variation in CdaA produced less c-di-AMP and was highly susceptible to CSP. Deletion of cabP and trkH restored the growth of these bacteria in medium with CSP. Overall, our study demonstrates a novel role for c-di-AMP in the competence program of S. pneumoniaeIMPORTANCE Genetic competence in bacteria leads to horizontal gene transfer, which can ultimately affect antibiotic resistance, adaptation to stress conditions, and virulence. While the mechanisms of pneumococcal competence signaling cascades have been well characterized, the molecular mechanism behind competence regulation is not fully understood. The bacterial second messenger c-di-AMP has previously been shown to play a role in bacterial physiology and pathogenesis. In this study, we provide compelling evidence for the interplay between c-di-AMP and the pneumococcal competence state. These findings not only attribute a new biological function to this dinucleotide as a regulator of competence, transformation, and survival under stress conditions in pneumococci but also provide new insights into how pneumococcal competence is modulated.

Dataset Information

Making and Breaking of an Essential Poison: the Cyclases and Phosphodiesterases That Produce and Degrade the Essential Second Messenger Cyclic di-AMP in Bacteria.

Publications

Making and Breaking of an Essential Poison: the Cyclases and Phosphodiesterases That Produce and Degrade the Essential Second Messenger Cyclic di-AMP in Bacteria.

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