Cyclic GMP-AMP synthase

cGAS complexed with dsDNA (Based on PDB 4O6A)

cGAS-cGAMP-STING pathway

Cyclic GMP-AMP synthase (cGAS, cGAMP synthase), belonging to the nucleotidyltransferase family, is a cytosolic DNA sensor that activates the type-I interferon pathway. It binds to microbial DNA as well as self DNA that invades the cytoplasm, and catalyzes cGAMP synthesis.^[1] cGAMP then functions as a second messenger that binds to and activates the endoplasmic reticulum protein STING to trigger type-I IFNs production.^{[2][3] [4]} Mice lacking cGAS were more vulnerable to lethal infection by DNA viruses.^[5] In addition, cGAS has been shown to be an innate immune sensor of retroviruses including HIV.^[6][7]

References

1. 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. PMID 23258413.
2. 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. PMID 23258412.
3. Gao, Pu; Ascano, Manuel; Wu, Yang; Barchet, Winfried; Gaffney, Barbara L.; Zillinger, Thomas; Serganov, Artem A.; Liu, Yizhou; Jones, Roger A.; Hartmann, Gunther; Tuschl, Thomas; Patel, Dinshaw J. (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. ISSN 0092-8674.
4. 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.
5. 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.
6. Gao, D; Wu, J; Wu, YT; Du, F; Aroh, C; Yan, N; Sun, L; Chen, ZJ (Aug 23, 2013). "Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses". Science 341 (6148): 903–6. doi:10.1126/science.1240933. PMC 3860819. PMID 23929945.
7. Lahaye, X; Satoh, T; Gentili, M; Cerboni, S; Conrad, C; Hurbain, I; El Marjou, A; Lacabaratz, C; Lelièvre, JD; Manel, N (Dec 12, 2013). "The Capsids of HIV-1 and HIV-2 Determine Immune Detection of the Viral cDNA by the Innate Sensor cGAS in Dendritic Cells". Immunity 39 (6): 1132–42. doi:10.1016/j.immuni.2013.11.002.