c-di-AMP: An Essential Molecule in the Signaling Pathways that Regulate the Viability and Virulence of Gram-Positive Bacteria
Abstract
:1. Introduction
2. Synthesis of c-di-AMP
2.1. DisA
2.2. CdaA
2.3. CdaS
2.4. CdaM
3. c-di-AMP Degradation
3.1. GdpP
3.2. PgpH
3.3. Pde2
4. c-di-AMP Binding Molecules
4.1. TetR-Family Transcription Factor, DarR
4.2. RCK_C Domain Protein KtrA
4.3. RCK_C Domain Protein CpaA
4.4. Histidine Kinase Protein, KdpD
4.5. PII-Like Signal Transduction Protein, PstA
4.6. KtrA Homolog Protein, CabP
4.7. CabPA and CabPB
4.8. LmPC
4.9. c-di-AMP Binding Riboswitches
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Bacterium | Function of c-di-AMP | c-di-AMP Synthesis Enzyme | c-di-AMP Degrading Enzyme | Phenotype Involved in an Altered Level of c-di-AMP | Ref. |
---|---|---|---|---|---|
Bacillus subtilis | DisA binds to DNA and maintains DNA integrity. CdaS regulates sporulation. CdaA regulates cell wall synthesis and ion channel homeostasis. | DisA, CdaA, and CdaS | GdpP and PgpH | DisA mutation: decreased DNA integrity CdaA mutation: impaired potassium ion channel system, weakened cell wall, increased resistance to antibiotics CdaS mutation: delayed sporulation. | [17,18,19,20] |
Listeria monocytogenes | Regulates cell wall homeostasis, resistance to acid, and carbon metabolism. | CdaA (DacA) | PdeA (GdpP homolog) and PgpH | Phosphodiesterase (PDE mutation: cell wall defects, increased resistance to antibiotics, low survival rate, sensitivity towards acid stress, altered interferon-ß stimulation in host cells. | [21] |
Mycobacterium tuberculosis | Functions are not fully understood yet, but DisA is predicted to be involved in DNA repair. | MtbDisA (DisA ortholog) | MtbPDE (Pde2 ortholog) | PDE mutation: reduced virulence. | [22] |
Staphylococcus aureus | Regulates cell wall synthesis, cell size, and potassium ion channel homeostasis. | CdaA | GdpP and Pde2 ortholog | gdpP deletion: smaller cell size, increased peptidoglycan cross-linking, increased resistance against cell wall and membrane targeting antibiotics, impaired potassium ion channel system. | [17] |
Streptococcus mutans | Regulates biofilm formation by binding to receptor proteins. | CdaA | PdeA (GdpP ortholog) and Pde2 | cda deletion: Increased sensitivity to hydrogen peroxide and enhanced polysaccharide synthesis. pdeA deletion: Increased biofilm formation. | [23,24] |
Streptococcus pneumoniae | Maintains potassium ion channel homeostasis. | CdaA | GdpP and Pde2 | PDE mutation: Impaired ability of long chain formation, decreased growth, and imbalance in the potassium ion channel. | [25] |
Streptococcus pyogenes | Regulates cell wall homeostasis and virulence gene expression. | CdaA (SpyDacA) | GdpP and Pde2 ortholog | gdpP deletion: Impaired biogenesis of SpeB, decreased virulence and increased antibiotic resistance. | [26] |
Streptococcus suis (SS2) | Promotes biofilm formation and increases virulence. | CdaA | GdpP and Pde2 ortholog | gdpP deletion: Reduced growth and reduced biofilm formation. | [27] |
Mycoplasma pneumoniae | Predicted to regulate potassium import through binding of KtrC. | CdaM | PdeM | cdaM and pdeM: essential for growth. | [28] |
c-di-AMP Receptor Proteins (Species Originally Identified in) | Location in the Cell | Protein Structure and Functional Domains | Protein Function | Phenotypes by Deletion or Overexpression of the Genes | References |
---|---|---|---|---|---|
DarR (Mycobacterium smegmatis,) | Cytoplasmic protein | DarR contains two domains: a C-terminal QacR-like domain, and an N-terminal TetR-like helix-turn-helix domain. The binding site of c-di-AMP has not been identified yet. | Transcriptional repressor for genes involved in ion transport, membrane lipid homeostasis, and stress response. | Deletion causes larger cell size. Overexpression is toxic to cells and causes reduced fatty acid metabolism. | [38,55] |
KtrA (S. aureus) | Cytoplasmic protein bound to the integral membrane protein KtrB | KtrA possesses two RCK domains, RCK_N and RCK_C. c-di-AMP binds to RCK_C. | KtrA-KtrB complex regulates the potassium ion channel opening and closing by changing their conformation following c-di-AMP binding. | Deletion causes sensitivity to osmotic stress and requires high levels of potassium for growth. | [17,32,58,61] |
CpaA (S. aureus) | Integral membrane protein | Twelve membrane-spanning region, RCK_N and RCK_C domain c-di-AMP binds to RCK_C. | A putative proton antiporter in the cell where intracellular protons are exchanged with potassium or sodium ions. | Not studied yet. | [17,32] |
KdpD (S. aureus) | Integral membrane protein | KdpD is a histidine kinase in a TCS. | Regulates a P-type ATP- dependent high-affinity potassium uptake system. | Deletion leads to low virulence and less survival. | [32,35,62,63] |
PstA (S. aureus) | Cytoplasmic protein | PII-like signal transduction protein with an unknown domain DUF970. | Unknown. | Not studied yet. | [64] |
CabP (S. pneumonaie) | Cytoplasmic protein | An octameric protein belonging to the Trk family Homolog of KtrA. Binds to the ortholog of KtrB SPD_0076. | A member of the potassium ion transporter. | CabP mutant exhibits low potassium ion uptake. | [25] |
CabPA (S. mutans) | Cytoplasmic protein | Trk family.protein. | Binds to VicR, facilitates biofilm formation. | Reduces biofilm formation ability. | [23] |
CabPB (S. mutans) | Cytoplasmic protein | Trk family protein. | Unknown. | CabPB mutant strains have not been studied yet. | [23] |
LmPC (L. monocytogenes) | Cytoplasmic protein | Pyruvate carboxylase family, c-di-AMP binds to the dimer interface. | Pyruvate carboxylase: ATP-dependent carboxylation of pyruvate to oxaloacetate. | Causes metabolic imbalance, lysis of bacterial cells during infection. | [48] |
CbpA, CbpB (L. monocytogenes) | Soluble proteins | Function unknown. | Unknown. | Not studied yet. | [48] |
NrdR (L. monocytogenes) | Cytoplasmic protein | Transcriptional repressor. | Transcriptional regulator. | Not studied yet. | [48] |
ydaO Riboswitches (B. subtilis) | Cytoplasmic RNA molecules | The regulatory RNA molecules contain a ligand-sensing domain and an expression platform. c-di-AMP binds to the ligand-sensing domain. | Regulates ion channels, responds to osmotic stress, and facilitates cell wall metabolism and sporulation. | Not essential. | [32,35,45,56,57,58,59,60] |
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Fahmi, T.; Port, G.C.; Cho, K.H. c-di-AMP: An Essential Molecule in the Signaling Pathways that Regulate the Viability and Virulence of Gram-Positive Bacteria. Genes 2017, 8, 197. https://doi.org/10.3390/genes8080197
Fahmi T, Port GC, Cho KH. c-di-AMP: An Essential Molecule in the Signaling Pathways that Regulate the Viability and Virulence of Gram-Positive Bacteria. Genes. 2017; 8(8):197. https://doi.org/10.3390/genes8080197
Chicago/Turabian StyleFahmi, Tazin, Gary C. Port, and Kyu Hong Cho. 2017. "c-di-AMP: An Essential Molecule in the Signaling Pathways that Regulate the Viability and Virulence of Gram-Positive Bacteria" Genes 8, no. 8: 197. https://doi.org/10.3390/genes8080197
APA StyleFahmi, T., Port, G. C., & Cho, K. H. (2017). c-di-AMP: An Essential Molecule in the Signaling Pathways that Regulate the Viability and Virulence of Gram-Positive Bacteria. Genes, 8(8), 197. https://doi.org/10.3390/genes8080197