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

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cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity.
EMBO Reports ( IF 6.5 ) Pub Date : 2019-03-14 , DOI: 10.15252/embr.201846293
Haipeng Liu _{1,

2} , Pedro Moura-Alves ₁ , Gang Pei ₁ , Hans-Joachim Mollenkopf ₃ , Robert Hurwitz ₄ , Xiangyang Wu ₂ , Fei Wang ₂ , Siyu Liu ₂ , Mingtong Ma ₂ , Yiyan Fei ₅ , Chenggang Zhu ₅ , Anne-Britta Koehler ₁ , Dagmar Oberbeck-Mueller ₁ , Karin Hahnke ₁ , Marion Klemm ₁ , Ute Guhlich-Bornhof ₁ , Baoxue Ge ₂ , Anne Tuukkanen ₆ , Michael Kolbe _{7,

8,

9,

10} , Anca Dorhoi _{11,

12,

13} , Stefan He Kaufmann _{11,

14}

Affiliation

Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Immunology, Microarray Core Facility, Max Planck Institute for Infection Biology, Berlin, Germany.
Protein Purification Core Facility, Max Planck Institute for Infection Biology, Berlin, Germany.
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.
European Molecular Biology Laboratory, Hamburg, Germany.
Max Planck Institute for Infection Biology, Structural Systems Biology, Berlin, Germany.
Department of Structural Infection Biology, Center for Structural Systems Biology, Hamburg, Germany.
Helmholtz Centre for Infection Research, Braunschweig, Germany.
Faculty of Mathematics, Informatics and Natural Sciences, University of Hamburg, Hamburg, Germany.
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany
Institute of Immunology, Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Griefswald-Insel Riems, Germany.
Faculty of Mathematics and Natural Sciences, University of Greifswald, Greifswald, Germany.
Faculty Fellow of the Hagler Institute for Advanced Study at Texas A&M University, College Station, TX, USA.

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.

中文翻译：

cGAS有助于感测细胞外环二核苷酸以激活先天免疫。

环二核苷酸（CDN）是原核生物和真核生物中重要的第二信使分子。在宿主细胞内，胞浆CDN可通过STING检测，并通过激活以I型干扰素（IFN）反应为特征的先天免疫来警告宿主。细胞外细菌和垂死细胞可以释放CDN，但是哺乳动物细胞对细胞外CDN（eCDN）的感应仍然难以捉摸。在这里，我们报道内吞作用促进eCDNs的内在化。DNA传感器cGAS有助于感测胞吞CDN，其核周积累以及随后STING依赖的I型IFN释放内在化CDN直接与cGAS结合，导致其二聚化，并形成cGAS / STING复合物，这可能激活下游信号传导。因此，

更新日期：2019-04-03

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