Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host-pathogen conflict

Elife. 2020 Nov 16;9:e59753. doi: 10.7554/eLife.59753.

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.

Keywords: STING; cGAMP; cGAS; immune evasion; infectious disease; microbiology; molecular biophysics; none; poxin; structural biology; virology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Cloning, Molecular
  • Deoxyribonucleases / genetics
  • Deoxyribonucleases / metabolism*
  • Evolution, Molecular
  • Genome
  • Lepidoptera / virology
  • Mammals / genetics
  • Mammals / metabolism
  • Models, Molecular
  • Nucleotides, Cyclic / genetics
  • Nucleotides, Cyclic / metabolism*
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism
  • Protein Conformation
  • RNA Viruses / enzymology
  • Vaccinia virus / genetics
  • Vaccinia virus / metabolism*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*

Substances

  • Nucleotides, Cyclic
  • Viral Proteins
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Deoxyribonucleases
  • Peptide Hydrolases