Identification of the Components Involved in Cyclic Di-AMP Signaling in Mycoplasma pneumoniae

Blötz, Cedric; Treffon, Katrin; Kaever, Volkhard; Schwede, Frank; Hammer, Elke; Stülke, Jörg

doi:10.3389/fmicb.2017.01328

Cited by 47 publications

(61 citation statements)

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“…Several different families of DACs have been identified, which all differ in their additional regulatory domain (Commichau et al, ; Corrigan & Gründling, ). So far, members of four bacterial DAC classes have been characterized in more detail: DisA (Witte et al, ), DacA/CdaA (Rosenberg et al, ), DacB/CdaS (Mehne et al, ), and CdaM (Blötz et al, ). Additionally, DAC activity has been demonstrated for a representative of the archaeal DacY/CdaZ class (Kellenberger et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that c-di-AMP released by intracellular pathogens, such as Listeria monocytogenes and Mycobacterium tuberculosis, activates the hosts' immune system by triggering a type I interferon response (Woodward, Iavarone, & Portnoy, 2010;Yang et al, 2014). Amongst cyclic nucleotide-based second messengers, c-di-AMP has a unique position as it is (under standard growth conditions) the only second messenger that is essential for the vast majority of species that produce it (Blötz et al, 2017;Chaudhuri et al, 2009;Luo & Helmann, 2012;Song et al, 2005;Whiteley, Pollock, & Portnoy, 2015). In addition, the intracellular level of c-di-AMP needs to be tightly regulated as both decreased and increased amounts of c-di-AMP in the cytoplasm cause severe negative effects on the cells (Gundlach et al, 2015;Huynh & Woodward, 2016).…”

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confidence: 99%

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Cyclic nucleotides in archaea: Cyclic di‐AMP in the archaeonHaloferax volcaniiand its putative role

et al. 2019

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The role of cyclic nucleotides as second messengers for intracellular signal transduction has been well described in bacteria. One recently discovered bacterial second messenger is cyclic di‐adenylate monophosphate (c‐di‐AMP), which has been demonstrated to be essential in bacteria. Compared to bacteria, significantly less is known about second messengers in archaea. This study presents the first evidence of in vivo presence of c‐di‐AMP in an archaeon. The model organism Haloferax volcanii was demonstrated to produce c‐di‐AMP. Its genome encodes one diadenylate cyclase (DacZ) which was shown to produce c‐di‐AMP in vitro. Similar to bacteria, the dacZ gene is essential and homologous overexpression of DacZ leads to cell death, suggesting the need for tight regulation of c‐di‐AMP levels. Such tight regulation often indicates the control of important regulatory processes. A central target of c‐di‐AMP signaling in bacteria is cellular osmohomeostasis. The results presented here suggest a comparable function in H. volcanii. A strain with decreased c‐di‐AMP levels exhibited an increased cell area in hypo‐salt medium, implying impaired osmoregulation. In summary, this study expands the field of research on c‐di‐AMP and its physiological function to archaea and indicates that osmoregulation is likely to be a common function of c‐di‐AMP in bacteria and archaea.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Cyclic nucleotides in archaea: Cyclic di‐AMP in the archaeonHaloferax volcaniiand its putative role

et al. 2019

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“…Cyclic di-AMP (c-di-AMP) plays a central role in the adaptation of bacteria to the environmental osmolarity (Witte et al, 2008;Commichau et al, 2015Commichau et al, , 2018Commichau et al, , 2019Fahmi et al, 2017;Stülke and Krüger, 2020). c-di-AMP is in fact essential for Bacillus subtilis, Lactococcus lactis, Listeria monocytogenes and other Gram-positive bacteria (Woodward et al, 2010;Corrigan et al, 2011;Luo and Helmann, 2012;Bai et al, 2013;Mehne et al, 2013;Witte et al, 2013;Whiteley et al, 2015;Rismondo et al, 2016) since the dinucleotide prevents the uptake of potassium and other osmolytes to toxic levels by direct binding to the respective transport systems Bai et al, 2014;Kim et al, 2015;Schuster et al, 2016;Blötz et al, 2017;Gundlach et al, 2017;Whiteley et al, 2017;Devaux et al, 2018;Pham et al, 2018;Zarella et al, 2018;Zeden et al, 2018;Gibhardt et al, 2019;Gundlach et al, 2019;Quintana et al, 2019). Recently, it has been shown that c-di-AMP is also involved in osmoadaptation of cyanobacteria and archaea (Rubin et al, 2018;Braun et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

An extracytoplasmic protein and a moonlighting enzyme modulate synthesis of c‐di‐AMP in Listeria monocytogenes

Gibhardt

Heidemann

Bremenkamp

et al. 2020

Environmental Microbiology

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Summary The second messenger cyclic di‐AMP (c‐di‐AMP) is essential for growth of many bacteria because it controls osmolyte homeostasis. c‐di‐AMP can regulate the synthesis of potassium uptake systems in some bacteria and it also directly inhibits and activates potassium import and export systems, respectively. Therefore, c‐di‐AMP production and degradation have to be tightly regulated depending on the environmental osmolarity. The Gram‐positive pathogen Listeria monocytogenes relies on the membrane‐bound diadenylate cyclase CdaA for c‐di‐AMP production and degrades the nucleotide with two phosphodiesterases. While the enzymes producing and degrading the dinucleotide have been reasonably well examined, the regulation of c‐di‐AMP production is not well understood yet. Here we demonstrate that the extracytoplasmic regulator CdaR interacts with CdaA via its transmembrane helix to modulate c‐di‐AMP production. Moreover, we show that the phosphoglucosamine mutase GlmM forms a complex with CdaA and inhibits the diadenylate cyclase activity in vitro. We also found that GlmM inhibits c‐di‐AMP production in L. monocytogenes when the bacteria encounter osmotic stress. Thus, GlmM is the major factor controlling the activity of CdaA in vivo. GlmM can be assigned to the class of moonlighting proteins because it is active in metabolism and adjusts the cellular turgor depending on environmental osmolarity.

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“…M. tuberculosis produces only MtDisA, a DisA homolog (29). Mycoplasma pneumoniae produces only CdaM, which is closely related to the DAC domain of CdaS in B. subtilis (30). The Gram-positive pathogens S. pyogenes, S. pneumoniae, S. aureus, and L. monocytogenes produce only DacA, which is the most common c-di-AMP synthase among the four DAC enzymes discovered so far, as it is found in a wide variety of bacteria (10,12,31).…”

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The Second Messenger c-di-AMP Regulates Diverse Cellular Pathways Involved in Stress Response, Biofilm Formation, Cell Wall Homeostasis, SpeB Expression, and Virulence in Streptococcus pyogenes

et al. 2019

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Cyclic di-AMP (c-di-AMP) is a recently discovered second messenger in bacteria. The cellular level of c-di-AMP in Streptococcus pyogenes is predicted to be controlled by the synthase DacA and two putative phosphodiesterases, GdpP and Pde2. To investigate the role of c-di-AMP in S. pyogenes, we generated null mutants in each of these proteins by gene deletion. Unlike those in other Gram-positive pathogens such as Staphylococcus aureus and Listeria monocytogenes, DacA in S. pyogenes was not essential for growth in rich media. The DacA null mutant presented a growth defect that manifested through an increased lag time, produced no detectable biofilm, and displayed increased susceptibility toward environmental stressors such as high salt, low pH, reactive oxygen radicals, and cell wall-targeting antibiotics, suggesting that c-di-AMP plays significant roles in crucial cellular processes involved in stress management. The Pde2 null mutant exhibited a lower growth rate and increased biofilm formation, and interestingly, these phenotypes were distinct from those of the null mutant of GdpP, suggesting that Pde2 and GdpP play distinctive roles in c-di-AMP signaling. DacA and Pde2 were critical to the production of the virulence factor SpeB and to the overall virulence of S. pyogenes, as both DacA and Pde2 null mutants were highly attenuated in a mouse model of subcutaneous infection. Collectively, these results show that c-di-AMP is an important global regulator and is required for a proper response to stress and for virulence in S. pyogenes, suggesting that its signaling pathway could be an attractive antivirulence drug target against S. pyogenes infections.

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Identification of the Components Involved in Cyclic Di-AMP Signaling in Mycoplasma pneumoniae

Cited by 47 publications

References 47 publications

Cyclic nucleotides in archaea: Cyclic di‐AMP in the archaeonHaloferax volcaniiand its putative role

Cyclic nucleotides in archaea: Cyclic di‐AMP in the archaeonHaloferax volcaniiand its putative role

An extracytoplasmic protein and a moonlighting enzyme modulate synthesis of c‐di‐AMP in Listeria monocytogenes

The Second Messenger c-di-AMP Regulates Diverse Cellular Pathways Involved in Stress Response, Biofilm Formation, Cell Wall Homeostasis, SpeB Expression, and Virulence in Streptococcus pyogenes

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