TY - JOUR TI - Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host–pathogen conflict AU - Eaglesham, James B AU - McCarty, Kacie L AU - Kranzusch, Philip J A2 - Akhmanova, Anna A2 - Elde, Nels C A2 - Elde, Nels C VL - 9 PY - 2020 DA - 2020/11/16 SP - e59753 C1 - eLife 2020;9:e59753 DO - 10.7554/eLife.59753 UR - https://doi.org/10.7554/eLife.59753 AB - 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. KW - poxin KW - cGAMP KW - cGAS KW - STING KW - immune evasion KW - virology JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -