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Structural mechanism of cytosolic DNA sensing by cGAS

Author

Listed:
  • Filiz Civril

    (Ludwig-Maximilians-University, 81377 Munich, Germany)

  • Tobias Deimling

    (Ludwig-Maximilians-University, 81377 Munich, Germany)

  • Carina C. de Oliveira Mann

    (Ludwig-Maximilians-University, 81377 Munich, Germany)

  • Andrea Ablasser

    (Institute for Clinical Chemistry & Clinical Pharmacology, Unit for Clinical Biochemistry, University Hospital, University of Bonn, 53127 Bonn, Germany)

  • Manuela Moldt

    (Ludwig-Maximilians-University, 81377 Munich, Germany)

  • Gregor Witte

    (Ludwig-Maximilians-University, 81377 Munich, Germany)

  • Veit Hornung

    (Institute for Clinical Chemistry & Clinical Pharmacology, Unit for Clinical Biochemistry, University Hospital, University of Bonn, 53127 Bonn, Germany)

  • Karl-Peter Hopfner

    (Ludwig-Maximilians-University, 81377 Munich, Germany
    Center for Integrated Protein Sciences, 81377 Munich, Germany)

Abstract

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.

Suggested Citation

  • Filiz Civril & Tobias Deimling & Carina C. de Oliveira Mann & Andrea Ablasser & Manuela Moldt & Gregor Witte & Veit Hornung & Karl-Peter Hopfner, 2013. "Structural mechanism of cytosolic DNA sensing by cGAS," Nature, Nature, vol. 498(7454), pages 332-337, June.
    • Handle: RePEc:nat:nature:v:498:y:2013:i:7454:d:10.1038_nature12305
    DOI: 10.1038/nature12305
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    Citations

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    Cited by:

    1. Tian-Chen Xiong & Ming-Cong Wei & Fang-Xu Li & Miao Shi & Hu Gan & Zhen Tang & Hong-Peng Dong & Tianzi Liuyu & Pu Gao & Bo Zhong & Zhi-Dong Zhang & Dandan Lin, 2022. "The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Xintao Tu & Ting-Ting Chu & Devon Jeltema & Kennady Abbott & Kun Yang & Cong Xing & Jie Han & Nicole Dobbs & Nan Yan, 2022. "Interruption of post-Golgi STING trafficking activates tonic interferon signaling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Shirin Fatma & Arpita Chakravarti & Xuankun Zeng & Raven H. Huang, 2021. "Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    4. Lina Wang & Siru Li & Kai Wang & Na Wang & Qiaoling Liu & Zhen Sun & Li Wang & Lulu Wang & Quentin Liu & Chengli Song & Caigang Liu & Qingkai Yang, 2022. "DNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    5. Xiaoquan Wang & Youqiao Wang & Anqi Cao & Qinhong Luo & Daoyuan Chen & Weiqi Zhao & Jun Xu & Qinkai Li & Xianzhang Bu & Junmin Quan, 2023. "Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Shuai Wu & Sandra B. Gabelli & Jungsan Sohn, 2024. "The structural basis for 2′−5′/3′−5′-cGAMP synthesis by cGAS," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    7. Jing Liu & Xia Bu & Chen Chu & Xiaoming Dai & John M. Asara & Piotr Sicinski & Gordon J. Freeman & Wenyi Wei, 2023. "PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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