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

Tiansheng ZhengPedro Moura-AlvesGang PeiHans-Joachim MollenkopfRobert HurwitzXiangyang WuFei WangSiyu LiuMingtong MaYiyan FeiChenggang ZhuAnne-Britta KoehlerDagmar Oberbeck-MuellerKarin HahnkeMarion KlemmUte Guhlich-BornhofBaoxue GeAnne TuukkanenMichael KolbeAnca DorhoiStefan H E Kaufmann
Published in: EMBO reports (2019)
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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