Journal
ELIFE
Volume 9, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.59753
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Funding
- Richard and Susan Smith Family Foundation
- Cancer Research Institute Clinic and Laboratory Integration Program
- Pew Charitable Trusts Biomedical Scholars Program
- Mark Foundation for Cancer Research
- Parker Institute for Cancer Immunotherapy
- National Institutes of Health [AI007245]
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DNA viruses in the family Poxviridae encode poxin enzymes that degrade the immune second messenger 2 03 0-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 2030-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.
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