Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides (CDNs) released during bacterial infection, resulting in the launch of an innate immune response involving the TIR family of NADases. Using a structural–biochemical approach, Philip Kranzusch and colleagues provide evidence that STING and its associated immune pathway originated in bacteria. They identify functional bacterial homologues of STING, encoded within prokaryotic defence islands that protect against phage infection. Crystal structures reveal a scaffold with high similarity to metazoan STING, and reveals specificity for the CDN cyclic di-GMP, which is synthesized by a neighbouring cGAS nucleotidyltransferase (CD-NTase) enzyme. They show that CDN recognition leads to TIR effector domain oligomerization and rapid cleavage of NAD+. Comparative structural analyses reveal that a STING homologue in molluscs has additional domains that suggest an evolutionary trajectory from bacteria, metazoans and humans. This work provides evidence for the conservation of the cGAS–STING pathway, which suggests a common antiviral innate immune response among organisms that has its roots in bacteria.
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