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

  1. James B Eaglesham
  2. Kacie L McCarty
  3. Philip J Kranzusch  Is a corresponding author
  1. Harvard Medical School, Dana-Farber Cancer Institute, United States

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.

Data availability

Diffraction data have been deposited in the PDB under the accession codes 6XB3, 6XB4, 6XB5, and 6XB6.

The following data sets were generated

Article and author information

Author details

  1. James B Eaglesham

    Microbiology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kacie L McCarty

    Microbiology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Philip J Kranzusch

    Microbiology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, United States
    For correspondence
    philip.kranzusch@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4943-733X

Funding

Richard and Susan Smith Family Foundation

  • Philip J Kranzusch

Cancer Research Institute (Clinic and Laboratory Integration Program)

  • Philip J Kranzusch

Pew Charitable Trusts (Biomedical Scholars Program)

  • Philip J Kranzusch

The Mark Foundation for Cancer Research (Emerging Leader Award)

  • Philip J Kranzusch

The Parker Institute for Cancer Immunotherapy

  • Philip J Kranzusch

National Institutes of Health (T32 Training Grant AI007245)

  • James B Eaglesham

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Nels C. Elde, University of Utah, United States

Publication history

  1. Received: June 8, 2020
  2. Accepted: November 12, 2020
  3. Accepted Manuscript published: November 16, 2020 (version 1)
  4. Version of Record published: November 25, 2020 (version 2)

Copyright

© 2020, Eaglesham et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. James B Eaglesham
  2. Kacie L McCarty
  3. Philip J Kranzusch
(2020)
Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host-pathogen conflict
eLife 9:e59753.
https://doi.org/10.7554/eLife.59753
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