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Nature Reviews. Microbiology May 2017Cyclic dinucleotides (CDNs) are highly versatile signalling molecules that control various important biological processes in bacteria. The best-studied example is cyclic... (Review)
Review
Cyclic dinucleotides (CDNs) are highly versatile signalling molecules that control various important biological processes in bacteria. The best-studied example is cyclic di-GMP (c-di-GMP). Known since the late 1980s, it is now recognized as a near-ubiquitous second messenger that coordinates diverse aspects of bacterial growth and behaviour, including motility, virulence, biofilm formation and cell cycle progression. In this Review, we discuss important new insights that have been gained into the molecular principles of c-di-GMP synthesis and degradation, which are mediated by diguanylate cyclases and c-di-GMP-specific phosphodiesterases, respectively, and the cellular functions that are exerted by c-di-GMP-binding effectors and their diverse targets. Finally, we provide a short overview of the signalling versatility of other CDNs, including c-di-AMP and cGMP-AMP (cGAMP).
Topics: Bacteria; Biofilms; Cyclic GMP; Dinucleoside Phosphates; Gene Expression Regulation, Bacterial; Nucleotides, Cyclic; Second Messenger Systems; Signal Transduction
PubMed: 28163311
DOI: 10.1038/nrmicro.2016.190 -
Journal of Bacteriology Jan 2016Cyclic di-GMP (c-di-GMP) synthetases and hydrolases (GGDEF, EAL, and HD-GYP domains) can be readily identified in bacterial genome sequences by using standard... (Review)
Review
Cyclic di-GMP (c-di-GMP) synthetases and hydrolases (GGDEF, EAL, and HD-GYP domains) can be readily identified in bacterial genome sequences by using standard bioinformatic tools. In contrast, identification of c-di-GMP receptors remains a difficult task, and the current list of experimentally characterized c-di-GMP-binding proteins is likely incomplete. Several classes of c-di-GMP-binding proteins have been structurally characterized; for some others, the binding sites have been identified; and for several potential c-di-GMP receptors, the binding sites remain to be determined. We present here a comparative structural analysis of c-di-GMP-protein complexes that aims to discern the common themes in the binding mechanisms that allow c-di-GMP receptors to bind it with (sub)micromolar affinities despite the 1,000-fold excess of GTP. The available structures show that most receptors use their Arg and Asp/Glu residues to bind c-di-GMP monomers, dimers, or tetramers with stacked guanine bases. The only exception is the EAL domains that bind c-di-GMP monomers in an extended conformation. We show that in c-di-GMP-binding signature motifs, Arg residues bind to the O-6 and N-7 atoms at the Hoogsteen edge of the guanine base, while Asp/Glu residues bind the N-1 and N-2 atoms at its Watson-Crick edge. In addition, Arg residues participate in stacking interactions with the guanine bases of c-di-GMP and the aromatic rings of Tyr and Phe residues. This may account for the presence of Arg residues in the active sites of every receptor protein that binds stacked c-di-GMP. We also discuss the implications of these structural data for the improved understanding of the c-di-GMP signaling mechanisms.
Topics: Bacteria; Bacterial Proteins; Cyclic GMP; Gene Expression Regulation, Bacterial; Protein Binding; Signal Transduction
PubMed: 26055114
DOI: 10.1128/JB.00333-15 -
Current Opinion in Microbiology Apr 2017The second messenger nucleotide cyclic dimeric guanosine monophosphate (c-di-GMP) governs many cellular processes in the facultative human pathogen Vibrio cholerae. This... (Review)
Review
The second messenger nucleotide cyclic dimeric guanosine monophosphate (c-di-GMP) governs many cellular processes in the facultative human pathogen Vibrio cholerae. This organism copes with changing environmental conditions in aquatic environments and during transitions to and from human hosts. Modulation of c-di-GMP allows V. cholerae to shift between motile and sessile stages of life, thus allowing adaptation to stressors and environmental conditions during its transmission cycle. The V. cholerae genome encodes a large set of proteins predicted to degrade and produce c-di-GMP. A subset of these enzymes has been demonstrated to control cellular processes - particularly motility, biofilm formation, and virulence - through transcriptional, post-transcriptional, and translational mechanisms. Recent studies have identified and characterized enzymes that modulate or sense c-di-GMP levels and have led towards mechanistic understanding of c-di-GMP regulatory circuits in V. cholerae.
Topics: Biofilms; Cyclic GMP; Gene Expression Regulation, Bacterial; Genome, Bacterial; Humans; Second Messenger Systems; Signal Transduction; Vibrio cholerae; Virulence
PubMed: 28171809
DOI: 10.1016/j.mib.2017.01.002 -
Current Opinion in Microbiology Apr 2016Alphaproteobacteria include many medically and environmentally important organisms. Despite the diversity of their niches and lifestyles, from free-living to... (Review)
Review
Alphaproteobacteria include many medically and environmentally important organisms. Despite the diversity of their niches and lifestyles, from free-living to host-associated, they usually rely on very similar mechanisms to control their cell cycles. Studies on Caulobacter crescentus still lay the foundation for understanding the molecular details of pathways regulating DNA replication and cell division and coordinating these two processes with other events of the cell cycle. This review highlights recent discoveries on the regulation and the mode of action of conserved global regulators and small molecules like c-di-GMP and (p)ppGpp, which play key roles in cell cycle control. It also describes several newly identified mechanisms that modulate cell cycle progression in response to stresses or environmental conditions.
Topics: Alphaproteobacteria; Bacterial Proteins; Cell Cycle; Cyclic GMP; Gene Expression Regulation, Bacterial
PubMed: 26871482
DOI: 10.1016/j.mib.2016.01.010 -
Biological Chemistry Nov 2020The second messenger cyclic di-GMP regulates a variety of processes in bacteria, many of which are centered around the decision whether to adopt a sessile or a motile... (Review)
Review
The second messenger cyclic di-GMP regulates a variety of processes in bacteria, many of which are centered around the decision whether to adopt a sessile or a motile life style. Regulatory circuits include pathogenicity, biofilm formation, and motility in a wide variety of bacteria, and play a key role in cell cycle progression in Caulobacter crescentus. Interestingly, multiple, seemingly independent c-di-GMP pathways have been found in several species, where deletions of individual c-di-GMP synthetases (DGCs) or hydrolases (PDEs) have resulted in distinct phenotypes that would not be expected based on a freely diffusible second messenger. Several recent studies have shown that individual signaling nodes exist, and additionally, that protein/protein interactions between DGCs, PDEs and c-di-GMP receptors play an important role in signaling specificity. Additionally, subcellular clustering has been shown to be employed by bacteria to likely generate local signaling of second messenger, and/or to increase signaling specificity. This review highlights recent findings that reveal how bacteria employ spatial cues to increase the versatility of second messenger signaling.
Topics: Caulobacter crescentus; Cyclic GMP; Signal Transduction
PubMed: 32918803
DOI: 10.1515/hsz-2020-0202 -
Microbiology (Reading, England) Jul 2013Signal transduction pathways involving the second messenger cyclic di-GMP [bis-(3'-5')-cyclic di-guanosine monophosphate] occur widely in bacteria where they act to link... (Review)
Review
Signal transduction pathways involving the second messenger cyclic di-GMP [bis-(3'-5')-cyclic di-guanosine monophosphate] occur widely in bacteria where they act to link perception of environmental or intracellular cues and signals to specific alterations in cellular function. Such alterations can contribute to bacterial lifestyle transitions including biofilm formation and virulence. The cellular levels of the nucleotide are controlled through the opposing activities of diguanylate cyclases (DGCs) and phosphodiesterases (PDEs). The GGDEF domain of DGCs catalyses the synthesis of cyclic di-GMP from GTP, whereas EAL or HD-GYP domains in different classes of PDE catalyse cyclic di-GMP degradation to pGpG and GMP. We are now beginning to understand how alterations in cyclic di-GMP exert a regulatory action through binding to diverse receptors or effectors that include a small 'adaptor' protein domain called PilZ, transcription factors and riboswitches. The regulatory action of enzymically active cyclic di-GMP signalling proteins is, however, not restricted to an influence on the level of nucleotide. Here, I will discuss our recent findings that highlight the role that protein-protein interactions involving these signalling proteins have in regulating functions that contribute to bacterial virulence.
Topics: Bacterial Proteins; Cyclic GMP; Gene Expression Regulation, Bacterial; Molecular Sequence Data; Protein Interaction Maps; Signal Transduction; Virulence; Xanthomonas campestris
PubMed: 23704785
DOI: 10.1099/mic.0.068189-0 -
Journal of Bacteriology Jan 2016The first International Symposium on c-Di-GMP Signaling in Bacteria (22 to 25 March 2015, Harnack-Haus, Berlin, Germany)brought together 131 molecular microbiologists... (Review)
Review
The first International Symposium on c-Di-GMP Signaling in Bacteria (22 to 25 March 2015, Harnack-Haus, Berlin, Germany)brought together 131 molecular microbiologists from 17 countries to discuss recent progress in our knowledge of bacterial nucleotide second messenger signaling. While the focus was on signal input, synthesis, degradation, and the striking diversity of the modes of action of the current second messenger paradigm, i.e., cyclic di-GMP (c-di-GMP), “classics” like cAMP and (p)ppGpp were also presented, in novel facets, and more recent “newcomers,” such as c-di-AMP and c-AMP-GMP, made an impressive appearance. A number of clear trends emerged during the 30 talks, on the 71 posters, and in the lively discussions, including (i)c-di-GMP control of the activities of various ATPases and phosphorylation cascades, (ii) extensive cross talk between c-di-GMP and other nucleotide second messenger signaling pathways, and (iii) a stunning number of novel effectors for nucleotide second messengers that surprisingly include some long-known master regulators of developmental pathways. Overall, the conference made it amply clear that second messenger signaling is currently one of the most dynamic fields within molecular microbiology,with major impacts in research fields ranging from human health to microbial ecology.
Topics: Bacteria; Bacterial Proteins; Cyclic GMP; Gene Expression Regulation, Bacterial; Second Messenger Systems; Signal Transduction
PubMed: 26055111
DOI: 10.1128/JB.00331-15 -
Methods in Molecular Biology (Clifton,... 2017The nearly ubiquitous bacterial second messenger cyclic di-GMP is involved in a multitude of fundamental physiological processes such as sessility/motility transition... (Review)
Review
The nearly ubiquitous bacterial second messenger cyclic di-GMP is involved in a multitude of fundamental physiological processes such as sessility/motility transition and the switch between the acute and chronic infection status, combined with cell cycle control. The discovery of cyclic di-GMP, though, has been an example par excellence of scientific serendipity. We recapitulate here its years-long discovery process as an activator of the cellulose synthase of the environmental bacterium Komagataeibacter xylinus and its consequences for follow-up research. Indeed, the discovery of cyclic di-GMP as a ubiquitous second messenger contributed to the change in perception of bacteria as simple unicellular organisms just randomly building-up multicellular communities. Subsequently, cyclic di-GMP also paved the way to the identification of other pro- and eukaryotic cyclic dinucleotide second messengers.
Topics: Bacteria; Bacterial Physiological Phenomena; Biofilms; Cyclic GMP; Eukaryotic Cells; Glucosyltransferases; History, 20th Century; History, 21st Century; Research; Second Messenger Systems
PubMed: 28889281
DOI: 10.1007/978-1-4939-7240-1_1 -
Wiley Interdisciplinary Reviews. RNA Jan 2018Signaling pathways allow bacteria to adapt to changing environments. For pathogenic bacteria, signaling pathways allow for timely expression of virulence factors and the... (Review)
Review
Signaling pathways allow bacteria to adapt to changing environments. For pathogenic bacteria, signaling pathways allow for timely expression of virulence factors and the repression of antivirulence factors within the mammalian host. As the bacteria exit the mammalian host, signaling pathways enable the expression of factors promoting survival in the environment and/or nonmammalian hosts. One such signaling pathway uses the dinucleotide cyclic-di-GMP (c-di-GMP), and many bacterial genomes encode numerous proteins that are responsible for synthesizing and degrading c-di-GMP. Once made, c-di-GMP binds to individual protein and RNA receptors to allosterically alter the macromolecule function to drive phenotypic changes. Each bacterial genome encodes unique sets of genes for c-di-GMP signaling and virulence factors so the regulation by c-di-GMP is organism specific. Recent works have pointed to evidence that c-di-GMP regulates virulence in different bacterial pathogens of mammalian hosts. In this review, we discuss the criteria for determining the contribution of signaling nucleotides to pathogenesis using a well-characterized signaling nucleotide, cyclic AMP (cAMP), in Pseudomonas aeruginosa. Using these criteria, we review the roles of c-di-GMP in mediating virulence and highlight common themes that exist among eight diverse pathogens that cause different diseases through different routes of infection and transmission. WIREs RNA 2018, 9:e1454. doi: 10.1002/wrna.1454 This article is categorized under: RNA in Disease and Development > RNA in Disease.
Topics: Allosteric Regulation; Animals; Clostridioides difficile; Cyclic GMP; Gene Expression Regulation, Bacterial; Gram-Negative Bacteria; Humans; Protein Binding; Signal Transduction; Virulence; Virulence Factors
PubMed: 28990312
DOI: 10.1002/wrna.1454 -
Biological Chemistry Nov 2020Cyclic-di-GMP (c-di-GMP) is a ubiquitous bacterial second messenger which has been associated with a motile to sessile lifestyle switch in many bacteria. Here, we review... (Review)
Review
Cyclic-di-GMP (c-di-GMP) is a ubiquitous bacterial second messenger which has been associated with a motile to sessile lifestyle switch in many bacteria. Here, we review recent insights into c-di-GMP regulated processes related to environmental adaptations in alphaproteobacterial rhizobia, which are diazotrophic bacteria capable of fixing nitrogen in symbiosis with their leguminous host plants. The review centers on Sinorhizobium meliloti, which in the recent years was intensively studied for its c-di-GMP regulatory network.
Topics: Cyclic GMP; Sinorhizobium meliloti
PubMed: 32990642
DOI: 10.1515/hsz-2020-0232