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EMBO Rep. 2019 Apr;20(4). pii: e46293. doi: 10.15252/embr.201846293. Epub 2019 Mar 14.

cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity.

Author information

1
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
2
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
3
Department of Immunology, Microarray Core Facility, Max Planck Institute for Infection Biology, Berlin, Germany.
4
Protein Purification Core Facility, Max Planck Institute for Infection Biology, Berlin, Germany.
5
Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Fudan University, Shanghai, China.
6
European Molecular Biology Laboratory, Hamburg, Germany.
7
Max Planck Institute for Infection Biology, Structural Systems Biology, Berlin, Germany.
8
Department of Structural Infection Biology, Center for Structural Systems Biology, Hamburg, Germany.
9
Helmholtz Centre for Infection Research, Braunschweig, Germany.
10
Faculty of Mathematics, Informatics and Natural Sciences, University of Hamburg, Hamburg, Germany.
11
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany anca.dorhoi@fli.de kaufmann@mpiib-berlin.mpg.de.
12
Institute of Immunology, Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Griefswald-Insel Riems, Germany.
13
Faculty of Mathematics and Natural Sciences, University of Greifswald, Greifswald, Germany.
14
Faculty Fellow of the Hagler Institute for Advanced Study at Texas A&M University, College Station, TX, USA.

Abstract

Cyclic dinucleotides (CDNs) are important second messenger molecules in prokaryotes and eukaryotes. Within host cells, cytosolic CDNs are detected by STING and alert the host by activating innate immunity characterized by type I interferon (IFN) responses. Extracellular bacteria and dying cells can release CDNs, but sensing of extracellular CDNs (eCDNs) by mammalian cells remains elusive. Here, we report that endocytosis facilitates internalization of eCDNs. The DNA sensor cGAS facilitates sensing of endocytosed CDNs, their perinuclear accumulation, and subsequent STING-dependent release of type I IFN Internalized CDNs bind cGAS directly, leading to its dimerization, and the formation of a cGAS/STING complex, which may activate downstream signaling. Thus, eCDNs comprise microbe- and danger-associated molecular patterns that contribute to host-microbe crosstalk during health and disease.

KEYWORDS:

cyclic dinucleotides; cyclic guanosine monophosphate–adenosine monophosphate synthase; endocytosis; pathogen‐associated molecular pattern

PMID:
30872316
PMCID:
PMC6446192
[Available on 2020-04-01]
DOI:
10.15252/embr.201846293

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