Person: Shao, Sichen
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Shao
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Sichen
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Shao, Sichen
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Publication STING Cyclic Dinucleotide Sensing Originated in Bacteria(Springer Science and Business Media LLC, 2020-09-02) Morehouse, Benjamin R.; Govande, Apurva A.; Millman, Adi; Keszei, Alexander F. A.; Lowey, Brianna; Ofir, Gal; Shao, Sichen; Sorek, Rotem; Kranzusch, Philip J.Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides released during bacterial infection and endogenous cyclic GMP–AMP signaling during viral infection and antitumor immunity1-5. STING shares no structural homology with other known signaling proteins6-9, limiting functional analysis and preventing explanation for the origin of cyclic dinucleotide signaling in mammalian innate immunity. Here we discover functional STING homologues encoded within prokaryotic defense islands and reveal a conserved mechanism of signal activation. Crystal structures of bacterial STING define a minimal homodimeric scaffold that selectively responds to c-di-GMP synthesized by a neighboring cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzyme. Bacterial STING domains couple cyclic dinucleotide recognition with protein filament formation to drive TIR effector domain oligomerization and rapid NAD+ cleavage. We reconstruct the evolutionary events following acquisition of STING into metazoan innate immunity and determine the structure of a full-length TIR-STING fusion from the Pacific oyster C. gigas. Comparative structural analysis demonstrates how metazoan-specific additions to the core STING scaffold enabled a switch from direct effector function to regulation of antiviral transcription. Together, our results explain the mechanism of STING-dependent signaling and reveal conservation of a functional cGAS-STING pathway in prokaryotic bacteriophage defense.