期刊
EMBO REPORTS
卷 20, 期 4, 页码 -出版社
WILEY
DOI: 10.15252/embr.201846293
关键词
cyclic dinucleotides; cyclic guanosine monophosphate-adenosine monophosphate synthase; endocytosis; pathogen-associated molecular pattern
资金
- Max Planck Society
- National Natural Science Foundation of China [81200003, 8170006, 81370108]
- Shanghai Pujiang Program [16PJ1408600]
- Shanghai Medical and Health Services Outstanding Youth Talent Program [2017YQ078]
- European Union's Seventh Framework Programmes (EU-FP7/2007-2013), ERC [311374]
- European Research Council (ERC) [311374] Funding Source: European Research Council (ERC)
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.
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