STING cyclic dinucleotide sensing originated in bacteria

Abstract

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 immunity 1 – 5 . STING shares no structural homology with other known signaling proteins 6 – 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.

Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host–pathogen conflict

“…Stable poxin–2′3′-cGAMP complex formation was assessed using an electrophoretic mobility shift assay as previously developed for the receptor STING ( Morehouse et al, 2020 ; Whiteley et al, 2019 ). All 2′3′-cGAMP-binding experiments were performed with catalytic inactive poxin mutants VACV poxin H17A, AcNPV poxin H46A, and T. ni poxin H56A to prevent cleavage.…”

The Third Man: DNA sensing as espionage in pulmonary vascular health and disease

“…Cyclic dinucleotide detection, we now know, originated in bacteria, with bacterial Stimulator of Interferon Genes (STING) being particularly adept at response to invader generation cyclic di-GMP. This is juxtaposed to the refined mammalian response primarily to the secondary intermediate cyclic GMP-AMP (cGAMP), and is believed to represent a prokaryotic defense against bacteriophages and viral invaders, cellular "spies" 75 . Humans do have some retention of the cellular machinery to respond to bacterial cyclic di-GMP, however, such as the oxireductase RECON-mediated activation of inflammatory lynchpin, NF-B 76 .…”

Immunology of COVID‐19

“…The sentinel infectivity test of placing a monkey in a cage at the entrance of a bat cage before entering it is a lively illustration of this principle. Comparing prokaryotic viral defence systems with those of animals is not so farfetched as recently demonstrated by the origin of the stimulator of interferon genes (STING) as an antiviral system shared by prokaryotes and mammals (Morehouse et al ., 2020). It might therefore not be exaggerated to invoke another hypothesis in prokaryotic viral ecology.…”