Abstract
DNA viruses in the family Poxviridae encode poxin enzymes that degrade the immune second messenger 2'3'-cGAMP to inhibit cGAS-STING immunity in mammalian cells. The closest homologs of poxin exist in the genomes of insect viruses suggesting a key mechanism of cGAS-STING evasion may have evolved outside of mammalian biology. Here we use a biochemical and structural approach to discover a broad family of 369 poxins encoded in diverse viral and animal genomes and define a prominent role for 2'3'-cGAMP cleavage in metazoan host-pathogen conflict. Structures of insect poxins reveal unexpected homology to flavivirus proteases and enable identification of functional self-cleaving poxins in RNA-virus polyproteins. Our data suggest widespread 2'3'-cGAMP signaling in insect antiviral immunity and explain how a family of cGAS-STING evasion enzymes evolved from viral proteases through gain of secondary nuclease activity. Poxin acquisition by poxviruses demonstrates the importance of environmental connections in shaping evolution of mammalian pathogens.
Highlights
The cyclic GMP–AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a major sensor of pathogen infection in mammalian cells where it functions to detect mislocalized cytosolic DNA exposed during infection (Ablasser and Chen, 2019)
The enormous diversity of poxin enzymes in insect pathogens and moth and butterfly genomes confirms a broad role for 2030-cGAMP degradation, and strongly suggests these genomes served as a source for emergence of poxins in mammalian poxviruses
To assess if amarillovirus poxins possess autoproteolytic cleavage activity, we focused on the Xingshan cricket virus (XCV) poxin enzyme capable of 2030-cGAMP cleavage and a divergent homolog from Shuangao lacewing virus 2 (SLV2) that readily expressed to high levels in E. coli (Figure 5—figure supplement 2A)
Summary
The cGAS-STING pathway is a major sensor of pathogen infection in mammalian cells where it functions to detect mislocalized cytosolic DNA exposed during infection (Ablasser and Chen, 2019). Poxviruses are large DNA viruses which replicate exclusively in the cytosol (Moss, 2013), and encode poxvirus immune nucleases (poxins) to degrade 2030-cGAMP and prevent STING activation (Figure 1A; Eaglesham et al, 2019). Vaccinia virus (VACV) poxin (encoded by the gene B2R) is sufficient to antagonize cGAS-STING signaling in cells and is necessary for effective viral replication in vivo. Crystal structures of VACV poxin in the pre- and post-reactive states revealed that catalysis proceeds through a metal-independent mechanism, contorting 2030-cGAMP into a conformation that activates the 20 hydroxyl for in-line cleavage of the 30–50 bond (Eaglesham et al, 2019)
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