STING Cyclic Dinucleotide Sensing Originated in Bacteria

• Published in: Nature
• Main Authors: Morehouse, Benjamin R., Govande, Apurva A., Millman, Adi, Keszei, Alexander F. A., Lowey, Brianna, Ofir, Gal, Shao, Sichen, Sorek, Rotem, Kranzusch, Philip J.
• Format: Article in Journal/Newspaper
• Language: English
• Published: Springer Science and Business Media LLC 2020
• Subjects: Multidisciplinary; Pacific; Pacific oyster
• Online Access: https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37372911; https://doi.org/10.1038/s41586-020-2719-5

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. Accepted Manuscript