1. cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity
- Author
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Mingtong Ma, Anne Tuukkanen, Xiangyang Wu, Anca Dorhoi, Karin Hahnke, Siyu Liu, Marion Klemm, Dagmar Oberbeck-Mueller, Hans-Joachim Mollenkopf, Haipeng Liu, Pedro Moura-Alves, Fei Wang, Ute Guhlich-Bornhof, Anne-Britta Koehler, Gang Pei, Stefan H. E. Kaufmann, Baoxue Ge, Michael Kolbe, Yiyan Fei, Robert Hurwitz, and Chenggang Zhu
- Subjects
0303 health sciences ,Innate immune system ,STING complex ,Chemistry ,Pathogen-associated molecular pattern ,media_common.quotation_subject ,Endocytosis ,Biochemistry ,Cell biology ,03 medical and health sciences ,Crosstalk (biology) ,0302 clinical medicine ,Second messenger system ,Genetics ,Extracellular ,Internalization ,Molecular Biology ,030217 neurology & neurosurgery ,030304 developmental biology ,media_common - 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.
- Published
- 2019