Structural mechanism of cytosolic DNA sensing by cGAS

By F. Civril, T. Deimling, C. C. de Oliveira Mann, A. Ablasser, Manuela Moldt, Gregor Witte, V. Hornung, K. Hopfner. Nature, 2013

810 citations recorded by the source corpus.

Cytosolic DNA arising from intracellular bacterial or viral infections is a powerful pathogen-associated molecular pattern (PAMP) that leads to innate immune host defence by the production of type I interferon and inflammatory cytokines. Recognition of cytosolic DNA by the recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of cGAMP to activate the stimulator of interferon genes (STING). Here we report the crystal structure of cGAS alone and in complex with DNA, ATP and GTP along with functional studies. Our results explain the broad DNA sensing specificity of cGAS, show how cGAS catalyses dinucleotide formation and indicate activation by a DNA-induced structural switch. cGAS possesses a remarkable structural similarity to the antiviral cytosolic double-stranded RNA sensor 2′-5′oligoadenylate synthase (OAS1), but contains a unique zinc thumb that recognizes B-form double-stranded DNA. Our results mechanistically unify dsRNA and dsDNA innate immune sensing by OAS1 and cGAS nucleotidyl transferases.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3fdc4daecbf5975c0d1a6861036af925bb608dd4

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Zhijian J. Chen
2. Y. Chiu
3. Xin Cai
4. G. Lessene
5. Shizuo Akira
6. G. Barber
7. N. Perkins
8. Tuo Li

In Molecular Biology

1. Zhijian J. Chen
2. Matthew E. Ritchie
3. Xin Cai
4. Marco J. Herold
5. D. Huang
6. Y. Chiu
7. G. Lessene

Citations in the corpus

• The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. (2014, positive): “Third, cGAS synthesized 2030-cGAMP for subsequent STING activation only in the presence of DNA, which is also supported by structural studies described below (Civril et al., 2013; Gao et al., 2013b; Sun et al., 2013).”
• Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production (2014, positive): “Recent evidence indicates that cGAS is activated via a direct interaction with cytosolic DNA (Civril et al., 2013; Sun et al., 2013).”
• IDO in the Tumor Microenvironment: Inflammation, Counter-regulation and Tolerance (2016, neutral): “Once bound to DNA, cGAS undergoes conformational changes that catalyze synthesis of the cyclic dinucleotide (CDN) cGAMP [61].”
• Cyclic GMP-AMP Synthase is Activated by Double-stranded DNA-Induced Oligomerization (2013, positive): “More compelling evidence about DNA binding-induced dimerization of cGAS comes from the seven different structures of mouse and porcine cGAS bound to dsDNA published recently (Civril et al., 2013; Gao et al., 2013a).”