The Innate Immune DNA Sensor cGAS Produces a Noncanonical Cyclic Dinucleotide that Activates Human STING

TLDR

Foreign DNA in the cytosol triggers a strong interferon response by activating cGAS, which synthesizes cyclic GMP‑AMP that binds and activates the adaptor protein STING. The study aimed to identify human STING variants that, despite poor responsiveness to canonical cGAMP, remain responsive to DNA and cGAS signaling. The authors discovered that cGAS generates a noncanonical cyclic dinucleotide, cyclic [G(2′‑5′)pA(3′‑5′)p], which potently activates diverse human STING variants and distinguishes them from bacterial 3′‑5′ cyclic dinucleotides, suggesting therapeutic potential.

Abstract

Highlights•Human STING variants respond poorly to cGAMP but still respond to cytosolic DNA•DNA sensing through cGAS leads to production of a noncanonical 2′-5′ linked cGAMP•STING variants respond robustly to 2′-5′ linked cGAMP and not canonical cGAMPSummaryThe presence of foreign DNA in the cytosol of mammalian cells elicits a potent antiviral interferon response. Recently, cytosolic DNA was proposed to induce the synthesis of cyclic GMP-AMP (cGAMP) upon binding to an enzyme called cGAMP synthase (cGAS). cGAMP activates an interferon response by binding to a downstream receptor called STING. Here, we identify natural variants of human STING (hSTING) that are poorly responsive to cGAMP yet, unexpectedly, are normally responsive to DNA and cGAS signaling. We explain this paradox by demonstrating that the cGAS product is actually a noncanonical cyclic dinucleotide, cyclic [G(2′-5′)pA(3′-5′)p], which contains a single 2′-5′ phosphodiester bond. Cyclic [G(2′-5′)pA(3′-5′)p] potently activates diverse hSTING receptors and, therefore, may be a useful adjuvant or immunotherapeutic. Our results indicate that hSTING variants have evolved to distinguish conventional (3′-5′) cyclic dinucleotides, known to be produced mainly by bacteria, from the noncanonical cyclic dinucleotide produced by mammalian cGAS.Graphical abstract