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

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.

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [1]
  1. Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States); Harvard Univ., Boston, MA (United States)
  2. Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1736294
Grant/Contract Number:  
AC02-06CH11357; AI007245; GM124165; GM103403; S10 RR029205
Resource Type:
Accepted Manuscript
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 9; Journal Issue: 2020; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Eaglesham, James B., McCarty, Kacie L., and Kranzusch, Philip J.. Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host–pathogen conflict. United States: N. p., 2020. Web. https://doi.org/10.7554/elife.59753.
Eaglesham, James B., McCarty, Kacie L., & Kranzusch, Philip J.. Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host–pathogen conflict. United States. https://doi.org/10.7554/elife.59753
Eaglesham, James B., McCarty, Kacie L., and Kranzusch, Philip J.. Mon . "Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host–pathogen conflict". United States. https://doi.org/10.7554/elife.59753. https://www.osti.gov/servlets/purl/1736294.
@article{osti_1736294,
title = {Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host–pathogen conflict},
author = {Eaglesham, James B. and McCarty, Kacie L. and Kranzusch, Philip J.},
abstractNote = {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.},
doi = {10.7554/elife.59753},
journal = {eLife},
number = 2020,
volume = 9,
place = {United States},
year = {2020},
month = {11}
}

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