A jack of all trades: the multiple roles of the unique essential second messenger cyclic di‐<scp>AMP</scp>

Commichau, Fabian M.; Dickmanns, Achim; Gundlach, Jan; Ficner, Ralf; Stülke, Jörg

doi:10.1111/mmi.13026

Cited by 128 publications

(123 citation statements)

References 90 publications

(181 reference statements)

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“…Since CdaS is expressed exclusively under conditions of sporulation, and since the c-di-AMP formed by this enzyme is implicated in spore germination (20), we can assume that CdaS produces a specific pool of c-di-AMP that is relevant only under very specific conditions. For CdaA and DisA, the data suggest a functional spe- cialization: while CdaA seems to be involved in the control of cell wall homeostasis, there is increasing support for the idea that DisA contributes to the control of DNA integrity and to DNA repair (5,13,15,51). The localizations of the two enzymes, in the membrane and attached to the DNA (51; the present study), are in excellent agreement with the differential functional assignments.…”

Section: Discussionsupporting

confidence: 75%

“…Cyclic di-AMP is unique among all known second messengers: B. subtilis and other firmicutes are not able to live without this signaling molecule (5). In this work, we discovered a second peculiarity of c-di-AMP: not only is this nucleotide essential, but at high levels it becomes toxic to cells, resulting in lysis or in the accumulation of mutations that inactivate the diadenylate cyclase CdaA or prevent its expression.…”

Section: Discussionmentioning

confidence: 78%

“…Interestingly, c-di-AMP is essential in all firmicutes that have been studied in this respect, among them the model organism Bacillus subtilis and the pathogens Staphylococcus aureus, Streptococcus pneumoniae, and Listeria monocytogenes (6)(7)(8)(9)(10). This makes c-di-AMP unique among all second messengers, since it is the only essential signaling nucleotide (5).…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

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

et al. 2015

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“…Since its discovery in 2008 (24), c-di-AMP has been reported to function in a variety of essential processes in various bacterial species (49,50). However, the role of c-di-AMP in the major human pathogen S. aureus has been limited to mediating ion homeostasis by regulating channel activity (11,36,37).…”

Section: Discussionmentioning

confidence: 99%

Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response

et al. 2016

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Staphylococcus aureus is a leading cause of community-and nosocomial-acquired infections, with a propensity for biofilm formation. S. aureus biofilms actively skew the host immune response toward an anti-inflammatory state; however, the biofilm effector molecules and the mechanism(s) of action responsible for this phenomenon remain to be fully defined. The essential bacterial second messenger cyclic diadenylate monophosphate (c-di-AMP) is an emerging pathogen-associated molecular pattern during intracellular bacterial infections, as c-di-AMP secretion into the infected host cytosol induces a robust type I interferon (IFN) response. Type I IFNs have the potential to exacerbate infectious outcomes by promoting anti-inflammatory effects; however, the type I IFN response to S. aureus biofilms is unknown. Additionally, while several intracellular proteins function as c-di-AMP receptors in S. aureus, it has yet to be determined if any extracellular role for c-di-AMP exists and its release during biofilm formation has not yet been demonstrated. This study examined the possibility that c-di-AMP released during S. aureus biofilm growth polarizes macrophages toward an anti-inflammatory phenotype via type I interferon signaling. DacA, the enzyme responsible for c-di-AMP synthesis in S. aureus, was highly expressed during biofilm growth, and 30 to 50% of total c-di-AMP produced from S. aureus biofilm was released extracellularly due to autolytic activity. S. aureus biofilm c-di-AMP release induced macrophage type I IFN expression via a STING-dependent pathway and promoted S. aureus intracellular survival in macrophages. These findings identify c-di-AMP as another mechanism for how S. aureus biofilms promote macrophage anti-inflammatory activity, which likely contributes to biofilm persistence. Staphylococcus aureus is a leading cause of prosthetic joint infections (1, 2), whereupon adherence to the implant surface facilitates biofilm formation. These infections are particularly challenging to treat and typically require a two-stage surgical process for insertion of a new device (1). Moreover, biofilms actively skew the host immune response toward an anti-inflammatory state, thereby contributing to the chronic nature of biofilm-mediated infections (3-5). This is evident by macrophage polarization toward an alternatively activated phenotype and the recruitment of myeloid-derived suppressor cells (MDSCs) (3,(6)(7)(8). While this immune deviation appears to be driven by S. aureus biofilm products, the effectors and their mechanism(s) of action remain to be fully identified.To further understand mechanisms of immune modification by S. aureus biofilms, we investigated the role of the essential bacterial second messenger cyclic diadenylate monophosphate (c-di-AMP), since it has been identified as an emerging pathogen-associated molecular pattern (PAMP) that influences immune responsiveness (9, 10). While c-di-AMP has been found to regulate many important functions in bacteria, including cell wall stress and peptidoglycan homeostas...

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“…Moreover, cyclic di-AMP (c-di-AMP) is a unique essential second messenger. The precise reason for the essentiality of this nucleotide is unknown, but c-di-AMP has been implicated in cell division and cell wall biosynthesis (164,165). Interestingly, c-di-AMP is not only essential but also toxic if it accumulates (166).…”

Section: Signaling In Cell Divisionmentioning

confidence: 99%

The Blueprint of a Minimal Cell: MiniBacillus

Reuß

Commichau

Gundlach

et al. 2016

Microbiol Mol Biol Rev

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SUMMARYBacillus subtilisis one of the best-studied organisms. Due to the broad knowledge and annotation and the well-developed genetic system, this bacterium is an excellent starting point for genome minimization with the aim of constructing a minimal cell. We have analyzed the genome ofB. subtilisand selected all genes that are required to allow life in complex medium at 37°C. This selection is based on the known information on essential genes and functions as well as on gene and protein expression data and gene conservation. The list presented here includes 523 and 119 genes coding for proteins and RNAs, respectively. These proteins and RNAs are required for the basic functions of life in information processing (replication and chromosome maintenance, transcription, translation, protein folding, and secretion), metabolism, cell division, and the integrity of the minimal cell. The completeness of the selected metabolic pathways, reactions, and enzymes was verified by the development of a model of metabolism of the minimal cell. A comparison of theMiniBacillusgenome to the recently reported designed minimal genome ofMycoplasma mycoidesJCVI-syn3.0 indicates excellent agreement in the information-processing pathways, whereas each species has a metabolism that reflects specific evolution and adaptation. The blueprint ofMiniBacilluspresented here serves as the starting point for a successive reduction of theB. subtilisgenome.

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A jack of all trades: the multiple roles of the unique essential second messenger cyclic di‐AMP

Cited by 128 publications

References 90 publications

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

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

Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response

The Blueprint of a Minimal Cell: MiniBacillus

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