Department of Microbiology, Harvard Medical School, Boston, United States; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, United States; Harvard PhD Program in Virology, Division of Medical Sciences, Harvard University, Boston, United States
Department of Microbiology, Harvard Medical School, Boston, United States; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, United States
Department of Microbiology, Harvard Medical School, Boston, United States; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, United States; Harvard PhD Program in Virology, Division of Medical Sciences, Harvard University, Boston, United States; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, United States
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.
