Cyclic di-AMP explained

Cyclic di-AMP (also called c-di-AMP and c-di-adenosine monophosphate) is a second messenger used in signal transduction in bacteria and archaea.[1] [2] [3] It is present in many Gram-positive bacteria, some Gram-negative species, and archaea of the phylum Euryarchaeota.It is one of many ubiquitous nucleotide second messengers including cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), guanosine pentaphosphate ((p)ppGpp), and cyclic di-GMP (c-di-GMP). c-di-AMP is a signaling nucleotide used in signaling pathways that trigger outputs by using receptor or target proteins to sense c-di-AMP concentrations in the cell.

In bacteria, cyclic di-AMP has been implicated in the control of growth, cell wall homeostasis, bacterial biofilm formation and virulence gene expression, heat and osmotic stress regulation and responses, sporulation, potassium transport, lysis, and antibiotic resistance.[4]

In humans, cyclic di-AMP has been implicated in the control of innate immune response and antiviral response against pathogens. The dinucleotide is also produced by numerous human pathogens, prompting the exploration of numerous c-di-AMP-regulating pathways both in humans and in bacteria.

Synthesis

Cyclic di-AMP is synthesized by a membrane-bound diadenylate cyclase (also called diadenylyl cyclase, CdA, and DAC) enzyme called CdaA (DacA). DacA condenses two ATP molecules to make c-di-AMP, releasing 2 pyrophosphates in the process.[5] [6] DacA requires a manganese or cobalt metal ion cofactor.[7] Most bacteria possess only one DAC enzyme, but some bacteria like B. subtilis possess two additional DAC enzymes (DisA and CdaS).

Cyclic di-AMP synthesis is inhibited by the GImM I154F mutation in the Lactococcus lactis bacterium. GImM is the phosphoglucosamine mutase enzyme that interconverts glucosamine-6-phosphate to glucosamine-1-phosphate to later form cell wall peptidoglycan and other polymers. The I154F mutation inhibits CdA activity by binding to it more strongly than wild-type GImM binds. Thus, GImM modulates c-di-AMP levels.

Synthesis is regulated a number of ways, including negative feedback inhibition and upregulation through a decrease in phosphodiesterase.

Degradation

Phosphodiesterase (PDE) enzymes degrade cyclic di-AMP to the linear molecule 5’-pApA (phosphadenylyl adenosine). 5'-pApA is also involved in a feedback inhibition loop that limits GdpP gene-dependent c-di-AMP hydrolysis, leading to elevated c-di-AMP levels.[8]

Regulation

Since cyclic di-AMP is a signaling nucleotide, it is presumed to adhere to the same regulation pathways, where environmental changes are sensed by synthesis or degradation enzymes, which modulate enzyme concentration. Regulation of c-di-AMP is critical because high c-di-AMP levels lead to abnormal physiology, growth defects, and reduced virulence in infection.[9] In some bacteria, loss of the phosphodiesterases that degrade c-di-AMP leads to cell death.[10] [11]

It is possible that in addition to enzymatic regulation, intracellular c-di-AMP levels can be regulated by active transport via multidrug resistance transporters that secrete c-di-AMP from the cytoplasm. Listeria monocytogenes has demonstrated such an effect.

At high concentrations, cyclic di-AMP binds to receptor and target proteins to control specific pathways. Elevated c-di-AMP levels have also been linked to increased resistance toward cell wall-damaging antibiotics (e.g. β-lactams) and reduced cellular turgor.[12] [13]

Fatty acid synthesis

Cyclic di-AMP has been linked to fatty acid synthesis regulation in Mycobacterium smegmatis, the growth of S. aureus in conditions of low potassium, the sensing of DNA integrity in B. subtilis, and cell wall homeostasis in multiple species.[14] [15] [16] [17]

Cell wall precursor, and thus peptidoglycan precursor, biosynthesis activity can also affect c-di-AMP levels in the cell. Similarly, c-di-AMP levels affect peptidoglycan precursor synthesis, suggesting a strong link between the c-di-AMP and peptidoglycan synthetic pathways.

Cell lysis and RNA synthesis

It is suggested that cyclic di-AMP is involved in the regulation of cell lysis. Studies have shown that bacterial mutant strains with low c-di-AMP levels lysed significantly faster than their parent strains.[18]

Cyclic di-AMP has also been linked to bacterial RNA synthesis inhibition. c-di-AMP stimulates the production of (p)ppGpp, an alarmone involved in bacterial stringent response.[19]

STING pathway

In eukaryotic cells, c-di-AMP is sensed and subsequently elicits a type I interferon (IFN) response, leading to the activation of defense mechanisms against viral infection. This detection and activation pathway involves STING, TBK1, and IRF3.[20] [21] c-di-AMP may also stimulate dendritic cells, leading to T cell activation.[22]

c-di-AMP activates the innate immune pathway STING (stimulator of interferon genes) to detect damaged DNA. The nucleotide either binds to the helicase DDX41, which in turn activates the STING pathway, or directly binds to the STING protein.[23] Cyclic di-AMP has been identified (along with 2’3’-cGAMP) as a ligand that induces closing of the STING dimer, leading to STING polymerization and pathway activation.[24] When a type I IFN response is not induced in response to c-di-AMP, STING is unable to relocate from the endoplasmic reticulum to the cytoplasm for pathway activation, suggesting that c-di-AMP is a predominant ligand in STING polymerization, and thus activation, via intracellular translocation.[25]

See also

Notes and References

  1. Dey B, Dey RJ, Cheung LS, Pokkali S, Guo H, Lee JH, Bishai WR . A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis . Nature Medicine . 21 . 4 . 401–6 . April 2015 . 25730264 . 4390473 . 10.1038/nm.3813 .
  2. Corrigan RM, Gründling A . Cyclic di-AMP: another second messenger enters the fray . Nature Reviews. Microbiology . 11 . 8 . 513–24 . August 2013 . 23812326 . 10.1038/nrmicro3069 . free . 29830881 . 10044/1/19649 .
  3. Braun F, Thomalla L, van der Does C, Quax TE, Allers T, Kaever V, Albers SV . Cyclic nucleotides in archaea: Cyclic di-AMP in the archaeon Haloferax volcanii and its putative role . MicrobiologyOpen . 8 . 9 . e00829 . September 2019 . 30884174 . 6741144 . 10.1002/mbo3.829 . free .
  4. Zhu Y, Pham TH, Nhiep TH, Vu NM, Marcellin E, Chakrabortti A, Wang Y, Waanders J, Lo R, Huston WM, Bansal N, Nielsen LK, Liang ZX, Turner MS . 6 . Cyclic-di-AMP synthesis by the diadenylate cyclase CdaA is modulated by the peptidoglycan biosynthesis enzyme GlmM in Lactococcus lactis . Molecular Microbiology . 99 . 6 . 1015–27 . March 2016 . 26585449 . 10.1111/mmi.13281 . 10453/41116 . 24427957 . free .
  5. Pham TH, Liang ZX, Marcellin E, Turner MS . Replenishing the cyclic-di-AMP pool: regulation of diadenylate cyclase activity in bacteria . Current Genetics . 62 . 4 . 731–738 . November 2016 . 27074767 . 10.1007/s00294-016-0600-8 . 1563228 .
  6. Commichau FM, Heidemann JL, Ficner R, Stülke J . Making and Breaking of an Essential Poison: the Cyclases and Phosphodiesterases That Produce and Degrade the Essential Second Messenger Cyclic di-AMP in Bacteria . Journal of Bacteriology . 201 . 1 . e00462–18, /jb/201/1/JB.00462–18.atom . January 2019 . 30224435 . 6287462 . 10.1128/JB.00462-18 . William . Margolin .
  7. Rosenberg J, Dickmanns A, Neumann P, Gunka K, Arens J, Kaever V, Stülke J, Ficner R, Commichau FM . 6 . Structural and biochemical analysis of the essential diadenylate cyclase CdaA from Listeria monocytogenes . The Journal of Biological Chemistry . 290 . 10 . 6596–606 . March 2015 . 25605729 . 4358292 . 10.1074/jbc.M114.630418 . free .
  8. Bowman L, Zeden MS, Schuster CF, Kaever V, Gründling A . New Insights into the Cyclic Di-adenosine Monophosphate (c-di-AMP) Degradation Pathway and the Requirement of the Cyclic Dinucleotide for Acid Stress Resistance in Staphylococcus aureus . The Journal of Biological Chemistry . 291 . 53 . 26970–26986 . December 2016 . 27834680 . 5207132 . 10.1074/jbc.M116.747709 . free .
  9. Huynh TN, Woodward JJ . Too much of a good thing: regulated depletion of c-di-AMP in the bacterial cytoplasm . Current Opinion in Microbiology . 30 . 22–29 . April 2016 . 26773214 . 4821758 . 10.1016/j.mib.2015.12.007 . Cell regulation .
  10. Gundlach J, Mehne FM, Herzberg C, Kampf J, Valerius O, Kaever V, Stülke J . An Essential Poison: Synthesis and Degradation of Cyclic Di-AMP in Bacillus subtilis . Journal of Bacteriology . 197 . 20 . 3265–74 . October 2015 . 26240071 . 4573722 . 10.1128/JB.00564-15 . G. A. . O'Toole .
  11. Blötz C, Treffon K, Kaever V, Schwede F, Hammer E, Stülke J . Mycoplasma pneumoniae . Frontiers in Microbiology . 8 . 1328 . 2017-07-13 . 28751888 . 5508000 . 10.3389/fmicb.2017.01328 . free .
  12. Wang X, Davlieva M, Reyes J, Panesso D, Arias CA, Shamoo Y . A Novel Phosphodiesterase of the GdpP Family Modulates Cyclic di-AMP Levels in Response to Cell Membrane Stress in Daptomycin-Resistant Enterococci . Antimicrobial Agents and Chemotherapy . 61 . 3 . e01422–16, /aac/61/3/e01422–16.atom . March 2017 . 28069645 . 5328519 . 10.1128/AAC.01422-16 .
  13. Commichau FM, Gibhardt J, Halbedel S, Gundlach J, Stülke J . A Delicate Connection: c-di-AMP Affects Cell Integrity by Controlling Osmolyte Transport . Trends in Microbiology . 26 . 3 . 175–185 . March 2018 . 28965724 . 10.1016/j.tim.2017.09.003 .
  14. Zhang L, Li W, He ZG . DarR, a TetR-like transcriptional factor, is a cyclic di-AMP-responsive repressor in Mycobacterium smegmatis . The Journal of Biological Chemistry . 288 . 5 . 3085–96 . February 2013 . 23250743 . 3561532 . 10.1074/jbc.M112.428110 . free .
  15. Corrigan RM, Campeotto I, Jeganathan T, Roelofs KG, Lee VT, Gründling A . Systematic identification of conserved bacterial c-di-AMP receptor proteins . Proceedings of the National Academy of Sciences of the United States of America . 110 . 22 . 9084–9 . May 2013 . 23671116 . 3670340 . 10.1073/pnas.1300595110 . 2013PNAS..110.9084C . free .
  16. Mehne FM, Gunka K, Eilers H, Herzberg C, Kaever V, Stülke J . Cyclic di-AMP homeostasis in bacillus subtilis: both lack and high level accumulation of the nucleotide are detrimental for cell growth . The Journal of Biological Chemistry . 288 . 3 . 2004–17 . January 2013 . 23192352 . 3548507 . 10.1074/jbc.M112.395491 . free .
  17. Luo Y, Helmann JD . Analysis of the role of Bacillus subtilis σ(M) in β-lactam resistance reveals an essential role for c-di-AMP in peptidoglycan homeostasis . Molecular Microbiology . 83 . 3 . 623–39 . February 2012 . 22211522 . 3306796 . 10.1111/j.1365-2958.2011.07953.x .
  18. Witte CE, Whiteley AT, Burke TP, Sauer JD, Portnoy DA, Woodward JJ . Cyclic di-AMP is critical for Listeria monocytogenes growth, cell wall homeostasis, and establishment of infection . mBio . 4 . 3 . e00282-13 . May 2013 . 23716572 . 3663569 . 10.1128/mBio.00282-13 . John . Mekalanos .
  19. Corrigan RM, Bowman L, Willis AR, Kaever V, Gründling A . Cross-talk between two nucleotide-signaling pathways in Staphylococcus aureus . The Journal of Biological Chemistry . 290 . 9 . 5826–39 . February 2015 . 25575594 . 4342491 . 10.1074/jbc.M114.598300 . free .
  20. Jin L, Hill KK, Filak H, Mogan J, Knowles H, Zhang B, Perraud AL, Cambier JC, Lenz LL . 6 . MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP . Journal of Immunology . 187 . 5 . 2595–601 . September 2011 . 21813776 . 3159690 . 10.4049/jimmunol.1100088 .
  21. Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE . 6 . STING is a direct innate immune sensor of cyclic di-GMP . Nature . 478 . 7370 . 515–8 . September 2011 . 21947006 . 3203314 . 10.1038/nature10429 . 2011Natur.478..515B .
  22. Škrnjug I, Rueckert C, Libanova R, Lienenklaus S, Weiss S, Guzmán CA . The mucosal adjuvant cyclic di-AMP exerts immune stimulatory effects on dendritic cells and macrophages . PLOS ONE . 9 . 4 . e95728 . 2014-04-22 . 24755640 . 3996008 . 10.1371/journal.pone.0095728 . 2014PLoSO...995728S . free .
  23. Parvatiyar K, Zhang Z, Teles RM, Ouyang S, Jiang Y, Iyer SS, Zaver SA, Schenk M, Zeng S, Zhong W, Liu ZJ, Modlin RL, Liu YJ, Cheng G . 6 . The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response . Nature Immunology . 13 . 12 . 1155–61 . December 2012 . 23142775 . 3501571 . 10.1038/ni.2460 .
  24. Ergun SL, Fernandez D, Weiss TM, Li L . STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition . English . Cell . 178 . 2 . 290–301.e10 . July 2019 . 31230712 . 10.1016/j.cell.2019.05.036 . free .
  25. Barker JR, Koestler BJ, Carpenter VK, Burdette DL, Waters CM, Vance RE, Valdivia RH . STING-dependent recognition of cyclic di-AMP mediates type I interferon responses during Chlamydia trachomatis infection . mBio . 4 . 3 . e00018-13 . April 2013 . 23631912 . 3663186 . 10.1128/mBio.00018-13 . Ronald . Taylor .

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