Cyclic Di-AMP Homeostasis in Bacillus subtilis

Mehne, Felix M.P.; Gunka, Katrin; Eilers, Hinnerk; Herzberg, Christina; Kaever, Volkhard; Stülke, Jörg

doi:10.1074/jbc.m112.395491

Cited by 185 publications

(200 citation statements)

References 52 publications

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“…It tightly regulates the expression of the glmS gene, which encodes an enzyme whose metabolic product is glucosamine-6-phosphate (GlcN6P). This gene is expressed at tightly regulated levels, and the glmS ribozymeriboswitch takes care of this by activating cleavage and degradation of the RNA upon GlcN6P binding (29,63). The total number of RNA segments that were annotated as intergenic regions is 505, and this corresponds to 32% of all RNA segments.…”

Section: Intergenic Regionsmentioning

confidence: 99%

“…subtilis contains approximately 35 riboswitches that, in total, regulate ϳ2% of all genes present in this bacterium (2, 61, 62) (see Table S1 in the supplemental material). Among other ligands, there are for instance riboswitches for flavin mononucleotide (FMN), lysine, guanine, S-adenosylmethionine (SAM), thiamine pyrophosphate, and the second messenger molecule cyclic-di-AMP (29,57,61,63,64) (see Table S1 in the supplemental material). Riboswitches display a wide diversity in their regulatory mechanisms, and even riboswitches of the same class can regulate their downstream genes in alternative ways.…”

Section: Figmentioning

confidence: 99%

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Regulatory RNAs in Bacillus subtilis: a Gram-Positive Perspective on Bacterial RNA-Mediated Regulation of Gene Expression

Mars

Nicolas

Denham

et al. 2016

Microbiol Mol Biol Rev

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SUMMARY Bacteria can employ widely diverse RNA molecules to regulate their gene expression. Such molecules include trans -acting small regulatory RNAs, antisense RNAs, and a variety of transcriptional attenuation mechanisms in the 5′ untranslated region. Thus far, most regulatory RNA research has focused on Gram-negative bacteria, such as Escherichia coli and Salmonella . Hence, there is uncertainty about whether the resulting insights can be extrapolated directly to other bacteria, such as the Gram-positive soil bacterium Bacillus subtilis . A recent study identified 1,583 putative regulatory RNAs in B. subtilis , whose expression was assessed across 104 conditions. Here, we review the current understanding of RNA-based regulation in B. subtilis , and we categorize the newly identified putative regulatory RNAs on the basis of their conservation in other bacilli and the stability of their predicted secondary structures. Our present evaluation of the publicly available data indicates that RNA-mediated gene regulation in B. subtilis mostly involves elements at the 5′ ends of mRNA molecules. These can include 5′ secondary structure elements and metabolite-, tRNA-, or protein-binding sites. Importantly, sense-independent segments are identified as the most conserved and structured potential regulatory RNAs in B. subtilis . Altogether, the present survey provides many leads for the identification of new regulatory RNA functions in B. subtilis .

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Section: Intergenic Regionsmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Regulatory RNAs in Bacillus subtilis: a Gram-Positive Perspective on Bacterial RNA-Mediated Regulation of Gene Expression

Mars

Nicolas

Denham

et al. 2016

Microbiol Mol Biol Rev

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“…This molecule is formed by many bacteria and archaea, including deltaproteobacteria, spirochaetes, actinobacteria, firmicutes, and cyanobacteria (see references 4 and 5 for recent reviews). 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).…”

mentioning

confidence: 99%

“…In this bacterium, the nucleotide is essential, but its excessive accumulation leads to a defect in cell wall biosynthesis resulting in impaired growth (7). Moreover, accumulation of c-di-AMP due to a loss of the phosphodiesterase GdpP results in increased resistance to ␤-lactam antibiotics that target cell wall synthesis (6).…”

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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“…However, many genes are redundant, and cellular functions can be achieved in completely different ways. The former is the case for DNA polymerase I (PolA) and its paralog YpcP or the diadenylate cyclase CdaA and one of the paralogs DisA and CdaS (36,37). Moreover, the same function may even be fulfilled by unrelated proteins, as observed for the membrane anchors for the Z-ring protein for cell division, FtsZ.…”

Section: Considerations For the Definition Of The Gene Set For A Minimentioning

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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Cyclic Di-AMP Homeostasis in Bacillus subtilis

Cited by 185 publications

References 52 publications

Regulatory RNAs in Bacillus subtilis: a Gram-Positive Perspective on Bacterial RNA-Mediated Regulation of Gene Expression

Regulatory RNAs in Bacillus subtilis: a Gram-Positive Perspective on Bacterial RNA-Mediated Regulation of Gene Expression

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

The Blueprint of a Minimal Cell: MiniBacillus

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