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Pharmacological Research Mar 2019Uridine adenosine tetraphosphate (UpA), biosynthesized by activation of vascular endothelial growth factor receptor (VEGFR) 2, was initially identified as a potent... (Review)
Review
Uridine adenosine tetraphosphate (UpA), biosynthesized by activation of vascular endothelial growth factor receptor (VEGFR) 2, was initially identified as a potent endothelium-derived vasoconstrictor in perfused rat kidney. Subsequently, the effect of UpA on vascular tone regulation was intensively investigated in arteries isolated from different vascular beds in rodents including rat pulmonary arteries, aortas, mesenteric and renal arteries as well as mouse aortas, in which UpA produces vascular contraction. In contrast, UpA produces vascular relaxation in porcine coronary small arteries and rat aortas. Intravenous infusion of UpA into conscious rats or mice decreases blood pressure, and intravenous bolus injection of UpA into anesthetized mice increases coronary blood flow, indicating an overall vasodilator influence in vivo. Although UpA is the first dinucleotide described that contains both purine and pyrimidine moieties, its cardiovascular effects are exerted mainly through activation of purinergic receptors. These effects not only encompass regulation of vascular tone, but also endothelial angiogenesis, smooth muscle cell proliferation and migration, and vascular calcification. Furthermore, this review discusses a potential role for UpA in cardiovascular pathophysiology, as plasma levels of UpA are elevated in juvenile hypertensive patients and UpA-mediated vascular purinergic signaling changes in cardiovascular disease such as hypertension, diabetes, atherosclerosis and myocardial infarction. Better understanding the vascular effect of the novel dinucleotide UpA and the purinergic signaling mechanisms mediating its effects will enhance its potential as target for treatment of cardiovascular disease.
Topics: Animals; Cardiovascular Physiological Phenomena; Cardiovascular System; Dinucleoside Phosphates; Humans; Receptors, Purinergic; Signal Transduction
PubMed: 30553823
DOI: 10.1016/j.phrs.2018.12.009 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Nov 2022Cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP) is a newly-discovered second messenger in bacteria and archaea. By directly binding to or affecting the... (Review)
Review
Cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP) is a newly-discovered second messenger in bacteria and archaea. By directly binding to or affecting the expression of target proteins, c-di-AMP regulates the physiological functions of bacteria, including maintaining osmotic pressure, balancing central metabolism, monitoring DNA damage, and controlling biofilm and spore formation. As a new pathogen-associated molecular pattern (PAMP), it binds to the host pattern recognition receptor (PRR), induces cyclic GMP-AMP synthase (cGAS)-STING signal axis to produce type Ⅰ interferon by activating the stimulator of interferon genes (STING), and promotes the secretion of inflammatory factors through nuclear factor κB (NF-κB) signaling pathway, thereby playing an important role in host immunity to bacterial infection and tumorigenesis. Due to its immunogenicity, c-di-AMP could be used as an immune adjuvant to provide new targets for the development of vaccines. However, the specific mechanism of action of c-di-AMP in host immunity awaits further exploration. Herein, we presented the structure and biological characteristics of c-di-AMP, and summarized the possible mechanism of c-di-AMP's regulation of host immune response. In addition, we also reported the latest findings on using c-di-AMP as an immune adjuvant in clinical treatment. Research on the function of c-di-AMP and its mechanism of action on host immune response provides new ideas for finding clinical solutions to bacterial resistance, infection control, tumor prevention, and vaccine development in the future.
Topics: Dinucleoside Phosphates; Bacteria; Biofilms; Signal Transduction
PubMed: 36443059
DOI: 10.12182/20220860102 -
Current Issues in Molecular Biology 2019Since the discovery of cyclic dimeric guanosine 3',5'-monophosphate (c-di-GMP) in 1987, the role of cyclic dinucleotides in signal pathways has been extensively studied.... (Review)
Review
Since the discovery of cyclic dimeric guanosine 3',5'-monophosphate (c-di-GMP) in 1987, the role of cyclic dinucleotides in signal pathways has been extensively studied. Many receptors and effectors of cyclic dinucleotides have been identified which play important roles in cellular processes. Example of such effectors include cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP)-binding proteins and endoplasmic reticulum membrane adaptor. Accumulating evidence indicate that cyclic dinucleotides act as second messengers that not only regulate the bacterial physiological processes but also affect host immune responses during infections. Streptococci species, which produce cyclic dinucleotides, are responsible for many human diseases. Numerous studies suggest that the cyclic dinucleotides are vital in signal transduction pathways as second messengers and influence the progression of infectious diseases. Here, we provide an overview of the molecular principles of cyclic dinucleotides synthesis and degradation and discuss recent progress on streptococcal signal transduction pathways by cyclic dinucleotide second messengers and their role in regulating host immune reaction. This review will provide a better understanding of the molecular mechanisms of streptococcal cyclic dinucleotide second messengers thereby revealing novel targets for preventing infections.
Topics: Bacterial Adhesion; Bacterial Proteins; Carrier Proteins; Cyclic AMP Response Element-Binding Protein; Cyclic GMP; Dinucleoside Phosphates; Gene Expression Regulation, Bacterial; Host-Pathogen Interactions; Humans; Intracellular Signaling Peptides and Proteins; Phenotype; Second Messenger Systems; Streptococcal Infections; Streptococcus pneumoniae; Streptococcus pyogenes; Virulence
PubMed: 31166170
DOI: 10.21775/cimb.032.087 -
British Journal of Pharmacology Aug 2015Vascular dysfunction plays a pivotal role in the development of systemic complications associated with arterial hypertension and diabetes. The endothelium, or more... (Review)
Review
Vascular dysfunction plays a pivotal role in the development of systemic complications associated with arterial hypertension and diabetes. The endothelium, or more specifically, various factors derived from endothelial cells tightly regulate vascular function, including vascular tone. In physiological conditions, there is a balance between endothelium-derived factors, that is, relaxing factors (endothelium-derived relaxing factors; EDRFs) and contracting factors (endothelium-derived contracting factors; EDCFs), which mediate vascular homeostasis. However, in disease states, such as diabetes and arterial hypertension, there is an imbalance between EDRF and EDCF, with a reduction of EDRF signalling and an increase of EDCF signalling. Among EDCFs, COX-derived vasoconstrictor prostanoids play an important role in the development of vascular dysfunction associated with hypertension and diabetes. Moreover, uridine adenosine tetraphosphate (Up4 A), identified as an EDCF in 2005, also modulates vascular function. However, the role of Up4 A in hypertension- and diabetes-associated vascular dysfunction is unclear. In the present review, we focused on experimental and clinical evidence that implicate these two EDCFs (vasoconstrictor prostanoids and Up4 A) in vascular dysfunction associated with hypertension and diabetes.
Topics: Animals; Diabetes Mellitus; Dinucleoside Phosphates; Endothelins; Gonadal Steroid Hormones; Humans; Hypertension; Myocytes, Smooth Muscle; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Vasoconstriction
PubMed: 26031319
DOI: 10.1111/bph.13205 -
Infection and Immunity Oct 2021Second messenger nucleotides are produced by bacteria in response to environmental stimuli and play a major role in the regulation of processes associated with bacterial...
Second messenger nucleotides are produced by bacteria in response to environmental stimuli and play a major role in the regulation of processes associated with bacterial fitness, including but not limited to osmoregulation, envelope homeostasis, central metabolism, and biofilm formation. In this study, we uncovered the biological significance of c-di-AMP in the opportunistic pathogen Enterococcus faecalis by isolating and characterizing strains lacking genes responsible for c-di-AMP synthesis () and degradation ( and ). Using complementary approaches, we demonstrated that either complete loss of c-di-AMP (Δ strain) or c-di-AMP accumulation (Δ, Δ, and Δ Δ strains) drastically impaired general cell fitness and virulence of E. faecalis. In particular, the Δ strain was highly sensitive to envelope-targeting antibiotics, was unable to multiply and quickly lost viability in human serum or urine , and was virtually avirulent in an invertebrate (Galleria mellonella) and in two catheter-associated mouse infection models that recapitulate key aspects of enterococcal infections in humans. In addition to evidence linking these phenotypes to altered activity of metabolite and peptide transporters and inability to maintain osmobalance, we found that the attenuated virulence of the Δ strain also could be attributed to a defect in Ebp pilus production and activity that severely impaired biofilm formation under both and conditions. Collectively, these results demonstrate that c-di-AMP signaling is essential for E. faecalis pathogenesis and a desirable target for drug development.
Topics: Animals; Biofilms; Dinucleoside Phosphates; Enterococcus faecalis; Fimbriae, Bacterial; Gene Expression Regulation, Bacterial; Gram-Positive Bacterial Infections; Humans; Virulence
PubMed: 34424750
DOI: 10.1128/IAI.00365-21 -
MBio Jan 2021The development of safe and effective vaccines against viruses is central to disease control. With advancements in DNA synthesis technology, the production of synthetic... (Review)
Review
The development of safe and effective vaccines against viruses is central to disease control. With advancements in DNA synthesis technology, the production of synthetic viral genomes has fueled many research efforts that aim to generate attenuated viruses by introducing synonymous mutations. Elucidation of the mechanisms underlying virus attenuation through synonymous mutagenesis is revealing interesting new biology that can be exploited for vaccine development. Here, we review recent advancements in this field of synthetic virology and focus on the molecular mechanisms of attenuation by genetic recoding of viruses. We highlight the action of the zinc finger antiviral protein (ZAP) and RNase L, two proteins involved in the inhibition of viruses enriched for CpG and UpA dinucleotides, that are often the products of virus recoding algorithms. Additionally, we discuss current challenges in the field as well as studies that may illuminate how other host functions, such as translation, are potentially involved in the attenuation of recoded viruses.
Topics: Animals; DNA Viruses; Dinucleoside Phosphates; Endoribonucleases; Genome, Viral; Humans; Silent Mutation; Vaccines, Attenuated; Viral Vaccines; Virus Replication; Viruses
PubMed: 33402534
DOI: 10.1128/mBio.02238-20 -
Viruses Sep 2021An evolutionary arms race occurs between viruses and hosts. Hosts have developed an array of antiviral mechanisms aimed at inhibiting replication and spread of viruses,... (Review)
Review
An evolutionary arms race occurs between viruses and hosts. Hosts have developed an array of antiviral mechanisms aimed at inhibiting replication and spread of viruses, reducing their fitness, and ultimately minimising pathogenic effects. In turn, viruses have evolved sophisticated counter-measures that mediate evasion of host defence mechanisms. A key aspect of host defences is the ability to differentiate between self and non-self. Previous studies have demonstrated significant suppression of CpG and UpA dinucleotide frequencies in the coding regions of RNA and small DNA viruses. Artificially increasing these dinucleotide frequencies results in a substantial attenuation of virus replication, suggesting dinucleotide bias could facilitate recognition of non-self RNA. The interferon-inducible gene, zinc finger antiviral protein (ZAP) is the host factor responsible for sensing CpG dinucleotides in viral RNA and restricting RNA viruses through direct binding and degradation of the target RNA. Herpesviruses are large DNA viruses that comprise three subfamilies, alpha, beta and gamma, which display divergent CpG dinucleotide patterns within their genomes. ZAP has recently been shown to act as a host restriction factor against human cytomegalovirus (HCMV), a beta-herpesvirus, which in turn evades ZAP detection by suppressing CpG levels in the major immediate-early transcript IE1, one of the first genes expressed by the virus. While suppression of CpG dinucleotides allows evasion of ZAP targeting, synonymous changes in nucleotide composition that cause genome biases, such as low GC content, can cause inefficient gene expression, especially in unspliced transcripts. To maintain compact genomes, the majority of herpesvirus transcripts are unspliced. Here we discuss how the conflicting pressures of ZAP evasion, the need to maintain compact genomes through the use of unspliced transcripts and maintaining efficient gene expression may have shaped the evolution of herpesvirus genomes, leading to characteristic CpG dinucleotide patterns.
Topics: Alphaherpesvirinae; Animals; Betaherpesvirinae; Dinucleoside Phosphates; Evolution, Molecular; Gammaherpesvirinae; Gene Expression; Genome, Viral; Herpesviridae; Host-Pathogen Interactions; Humans; Interferons; RNA Splicing; RNA, Viral; RNA-Binding Proteins; Signal Transduction; Viral Proteins
PubMed: 34578438
DOI: 10.3390/v13091857 -
Journal of Bacteriology Jan 2019Cyclic 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... (Review)
Review
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 , 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.
Topics: Adenylyl Cyclases; Bacillus subtilis; Dinucleoside Phosphates; Phosphoric Diester Hydrolases; Protein Domains
PubMed: 30224435
DOI: 10.1128/JB.00462-18 -
Current Genetics Nov 2016Bacteria can sense environmental cues and alter their physiology accordingly through the use of signal transduction pathways involving second messenger nucleotides. One... (Review)
Review
Bacteria can sense environmental cues and alter their physiology accordingly through the use of signal transduction pathways involving second messenger nucleotides. One broadly conserved second messenger is cyclic-di-AMP (c-di-AMP) which regulates a range of processes including cell wall homeostasis, potassium uptake, DNA repair, fatty acid synthesis, biofilm formation and central metabolism in bacteria. The intracellular pool of c-di-AMP is maintained by the activities of diadenylate cyclase (DAC) and phosphodiesterase (PDE) enzymes, as well as possibly via c-di-AMP export. Whilst extracellular stimuli regulating c-di-AMP levels in bacteria are poorly understood, recent work has identified effector proteins which directly interact and alter the activity of DACs. These include the membrane bound CdaR and the phosphoglucosamine mutase GlmM which both bind directly to the membrane bound CdaA DAC and the recombination protein RadA which binds directly to the DNA binding DisA DAC. The genes encoding these multiprotein complexes are co-localised in many bacteria providing further support for their functional connection. The roles of GlmM in peptidoglycan synthesis and RadA in Holliday junction intermediate processing suggest that c-di-AMP synthesis by DACs will be responsive to these cellular activities. In addition to these modulatory interactions, permanent dysregulation of DAC activity due to suppressor mutations can occur during selection to overcome growth defects, rapid cell lysis and osmosensitivity. DACs have also been investigated as targets for the development of new antibiotics and several small compound inhibitors have recently been identified. This review aims to provide an overview of how c-di-AMP synthesis by DACs can be regulated.
Topics: Bacteria; Bacterial Proteins; Dinucleoside Phosphates; Enzyme Inhibitors; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Mutation; Phosphorus-Oxygen Lyases; Protein Binding; Repressor Proteins; Signal Transduction
PubMed: 27074767
DOI: 10.1007/s00294-016-0600-8 -
Cyclic di-AMP, a second messenger of primary importance: tertiary structures and binding mechanisms.Nucleic Acids Research Apr 2020Cyclic diadenylate (c-di-AMP) is a widespread second messenger in bacteria and archaea that is involved in the maintenance of osmotic pressure, response to DNA damage,... (Review)
Review
Cyclic diadenylate (c-di-AMP) is a widespread second messenger in bacteria and archaea that is involved in the maintenance of osmotic pressure, response to DNA damage, and control of central metabolism, biofilm formation, acid stress resistance, and other functions. The primary importance of c-di AMP stems from its essentiality for many bacteria under standard growth conditions and the ability of several eukaryotic proteins to sense its presence in the cell cytoplasm and trigger an immune response by the host cells. We review here the tertiary structures of the domains that regulate c-di-AMP synthesis and signaling, and the mechanisms of c-di-AMP binding, including the principal conformations of c-di-AMP, observed in various crystal structures. We discuss how these c-di-AMP molecules are bound to the protein and riboswitch receptors and what kinds of interactions account for the specific high-affinity binding of the c-di-AMP ligand. We describe seven kinds of non-covalent-π interactions between c-di-AMP and its receptor proteins, including π-π, C-H-π, cation-π, polar-π, hydrophobic-π, anion-π and the lone pair-π interactions. We also compare the mechanisms of c-di-AMP and c-di-GMP binding by the respective receptors that allow these two cyclic dinucleotides to control very different biological functions.
Topics: Animals; Dinucleoside Phosphates; Molecular Conformation; Riboswitch; Second Messenger Systems; Signal Transduction
PubMed: 32095817
DOI: 10.1093/nar/gkaa112