Cyclic guanosine monophosphate–adenosine monophosphate

Cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, cGAMP) is the first cyclic di-nucleotide found in metazoa.[1] In mammalian cells, cGAMP is synthesized by cyclic GMP-AMP synthase (cGAS) from ATP and GTP upon cytosolic DNA stimulation.[2] cGAMP produced by cGAS contains mixed phosphodiester linkages, with one between 2'-OH of GMP and 5'-phosphate of AMP and the other between 3'-OH of AMP and 5'-phosphate of GMP.[3][4][5][6]

Cyclic guanosine monophosphate–adenosine monophosphate
Names
Other names
cGAMP; cyclic GMP-AMP; cGAMP(2'-5'); cyclic Gp(2'-5')Ap(3'-5')
Identifiers
3D model (JSmol)
ChEBI
KEGG
Properties
C20H24N10O13P2
Molar mass 674.417 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

This molecule, referred to as 2′3′-cGAMP (cyclic [G(2’,5’)pA(3’,5’)p]), functions as an endogenous second messenger inducing STING-dependent type I interferon response.[1][3] cGAMP has also been shown to be an effective adjuvant that boosts the production of antigen-specific antibodies and T cell responses in mice.[7] cGAMP exercises antiviral functions in the cell where it is produced, but can also cross cell membranes by passive diffusion to exert effects on neighboring cells.[8] It may even be packaged into lentivirus (such as HIV-1), poxvirus and herpes virus, and under cell culture conditions has been found to transmit an antiviral signal to the cells infected with these viruses; however, there is reason to think that at least HIV is capable of evading this mechanism by some means.[8]

In recent years, cGAMP signalling has been identified in prokaryotes including Vibrio cholerae which express a bacterial analogue of cGAS. In these organisms, cGAS is encoded as part of an operon alongside cGAMP-activated phospholipases (e.g. CapV in V. cholerae). During infection by bacteriophage, cGAS is activated and cGAMP is synthesised, activating CapV which degrades the cell's membrane and triggers cell death before the phage can complete its replicatory cycle.[9]

References
  1. Wu, J; Sun, L; Chen, X; Du, F; Shi, H; Chen, C; Chen, ZJ (Dec 20, 2012). "Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA". Science. 339 (6121): 826–30. doi:10.1126/science.1229963. PMC 3855410. PMID 23258412.
  2. Sun, L; Wu, J; Du, F; Chen, X; Chen, ZJ (Dec 20, 2012). "Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway". Science. 339 (6121): 786–91. doi:10.1126/science.1232458. PMC 3863629. PMID 23258413.
  3. Zhang, X; Shi, H; Wu, J; Zhang, X; Sun, L; Chen, C; Chen, ZJ (Jun 3, 2013). "Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High-Affinity Ligand for STING". Molecular Cell. 51 (2): 226–235. doi:10.1016/j.molcel.2013.05.022. PMC 3808999. PMID 23747010.
  4. Gao, P; Ascano, M; Wu, Y; Barchet, W; Gaffney, BL; et al. (May 3, 2013). "Cyclic [G(2′,5′)pA(3′,5′)p] Is the Metazoan Second Messenger Produced by DNA-Activated Cyclic GMP-AMP Synthase". Cell. 153 (5): 1094–1107. doi:10.1016/j.cell.2013.04.046. PMC 4382009. PMID 23647843.
  5. Ablasser, A; Goldeck, M; Cavlar, T; Deimling, T; Witte, G; Röhl, I; Hopfner, KP; Ludwig, J; Hornung, V (Jun 20, 2013). "cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING". Nature. 498 (7454): 380–384. doi:10.1038/nature12306. PMC 4143541. PMID 23722158.
  6. Diner, EJ; Burdette, DL; Wilson, SC; Monroe, KM; Kellenberger, CA; Hyodo, M; Hayakawa, Y; Hammond, MC; Vance, RE (May 23, 2013). "The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING". Cell Reports. 3 (5): 1355–61. doi:10.1016/j.celrep.2013.05.009. PMC 3706192. PMID 23707065.
  7. Li, XD; Wu, J; Gao, D; Wang, H; Sun, L; Chen, ZJ (Sep 20, 2013). "Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects". Science. 341 (6152): 1390–4. doi:10.1126/science.1244040. PMC 3863637. PMID 23989956.
  8. John W. Schoggins (2015-09-11). "Viruses carry antiviral cargo". Science. 349 (6253): 1186–1187. doi:10.1126/science.aad0942.
  9. Cohen, Daniel; Melamed, Sarah; Millman, Adi; Shulman, Gabriela; Oppenheimer-Shaanan, Yaara; Kacen, Assaf; Doron, Shany; Amitai, Gil; Sorek, Rotem (October 2019). "Cyclic GMP–AMP signalling protects bacteria against viral infection". Nature. 574 (7780): 691–695. doi:10.1038/s41586-019-1605-5. ISSN 1476-4687.
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