cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity
cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity
复制标题
cGAS 促进细胞外环状二核苷酸的传感，从而激活先天免疫
DOI：
10.15252/embr.201846293
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发表时间：
2019-04-01
期刊：
影响因子：
7.7
通讯作者：
Kaufmann, Stefan H. E.
中科院分区：
文献类型：
--
作者：
Liu, Haipeng;Moura-Alves, Pedro;Kaufmann, Stefan H. E.
环二核苷酸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，胞质cdn被STING检测到，并通过激活以I型干扰素（IFN）应答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，但哺乳动物细胞对细胞外cdn （ecdn）的感知尚不明确。在这里，我们报告了内吞作用促进ecdn的内化。DNA传感器cGAS有助于感知内吞的cdn，它们在核周围的积累，以及随后的STING依赖性I型IFN的释放。内化的cdn直接结合cGAS，导致其二聚化，并形成cGAS/STING复合物，可能激活下游信号。因此，ecdn包含微生物和危险相关的分子模式，在健康和疾病期间促进宿主-微生物串扰。
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.