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:
-
- Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States); Harvard Univ., Boston, MA (United States)
- 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. doi: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 = {Mon Nov 16 00:00:00 EST 2020},
month = {Mon Nov 16 00:00:00 EST 2020}
}
Works referenced in this record:
cGAS and CD-NTase enzymes: structure, mechanism, and evolution
journal, December 2019
- Kranzusch, Philip J.
- Current Opinion in Structural Biology, Vol. 59
Expanding Repertoire of Plant Positive-Strand RNA Virus Proteases
journal, January 2019
- Mann, Krin; Sanfaçon, Hélène
- Viruses, Vol. 11, Issue 1
A high‐quality chromosome‐level genome assembly of a generalist herbivore, Trichoplusia ni
journal, January 2019
- Chen, Wenbo; Yang, Xiaowei; Tetreau, Guillaume
- Molecular Ecology Resources, Vol. 19, Issue 2
Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection
journal, September 2020
- Hernáez, Bruno; Alonso, Graciela; Georgana, Iliana
- Science Advances, Vol. 6, Issue 38
Whole Genome Sequence of the Parasitoid Wasp Microplitis demolitor That Harbors an Endogenous Virus Mutualist
journal, July 2018
- Burke, Gaelen R.; Walden, Kimberly K. O.; Whitfield, James B.
- G3: Genes|Genomes|Genetics, Vol. 8, Issue 9
The genome sequence of Pseudoplusia includens single nucleopolyhedrovirus and an analysis of p26 gene evolution in the baculoviruses
journal, January 2015
- Craveiro, Saluana R.; Inglis, Peter W.; Togawa, Roberto C.
- BMC Genomics, Vol. 16, Issue 1
Serine peptidases: Classification, structure and function
journal, February 2008
- Page, M. J.; Di Cera, E.
- Cellular and Molecular Life Sciences, Vol. 65, Issue 7-8
New Algorithms and Methods to Estimate Maximum-Likelihood Phylogenies: Assessing the Performance of PhyML 3.0
journal, March 2010
- Guindon, Stéphane; Dufayard, Jean-François; Lefort, Vincent
- Systematic Biology, Vol. 59, Issue 3
InterProScan: protein domains identifier
journal, July 2005
- Quevillon, E.; Silventoinen, V.; Pillai, S.
- Nucleic Acids Research, Vol. 33, Issue Web Server
Virome Analysis of Aphid Populations That Infest the Barley Field: The Discovery of Two Novel Groups of Nege/Kita-Like Viruses and Other Novel RNA Viruses
journal, April 2020
- Kondo, Hideki; Fujita, Miki; Hisano, Hiroshi
- Frontiers in Microbiology, Vol. 11
Bacterial cGAS-like enzymes synthesize diverse nucleotide signals
journal, February 2019
- Whiteley, Aaron T.; Eaglesham, James B.; de Oliveira Mann, Carina C.
- Nature, Vol. 567, Issue 7747
Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway
journal, December 2012
- Sun, L.; Wu, J.; Du, F.
- Science, Vol. 339, Issue 6121
SLC19A1 transports immunoreactive cyclic dinucleotides
journal, September 2019
- Luteijn, Rutger D.; Zaver, Shivam A.; Gowen, Benjamin G.
- Nature, Vol. 573, Issue 7774
The Innate Immune DNA Sensor cGAS Produces a Noncanonical Cyclic Dinucleotide that Activates Human STING
journal, May 2013
- Diner, Elie J.; Burdette, Dara L.; Wilson, Stephen C.
- Cell Reports, Vol. 3, Issue 5
Global Organization and Proposed Megataxonomy of the Virus World
journal, March 2020
- Koonin, Eugene V.; Dolja, Valerian V.; Krupovic, Mart
- Microbiology and Molecular Biology Reviews, Vol. 84, Issue 2
The Phyre2 web portal for protein modeling, prediction and analysis
journal, May 2015
- Kelley, Lawrence A.; Mezulis, Stefans; Yates, Christopher M.
- Nature Protocols, Vol. 10, Issue 6
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs
journal, September 1997
- Altschul, Stephen F.; Madden, Thomas L.; Schäffer, Alejandro A.
- Nucleic Acids Research, Vol. 25, Issue 17, p. 3389-3402
cGAS in action: Expanding roles in immunity and inflammation
journal, March 2019
- Ablasser, Andrea; Chen, Zhijian J.
- Science, Vol. 363, Issue 6431
SignalP 5.0 improves signal peptide predictions using deep neural networks
journal, February 2019
- Almagro Armenteros, José Juan; Tsirigos, Konstantinos D.; Sønderby, Casper Kaae
- Nature Biotechnology, Vol. 37, Issue 4
Poxvirus DNA Replication
journal, July 2013
- Moss, B.
- Cold Spring Harbor Perspectives in Biology, Vol. 5, Issue 9
Gene Acquisition Convergence between Entomopoxviruses and Baculoviruses
journal, April 2015
- Thézé, Julien; Takatsuka, Jun; Nakai, Madoka
- Viruses, Vol. 7, Issue 4
Genomic and Proteomic Analyses Indicate that Banchine and Campoplegine Polydnaviruses Have Similar, if Not Identical, Viral Ancestors
journal, June 2015
- Béliveau, Catherine; Cohen, Alejandro; Stewart, Don
- Journal of Virology, Vol. 89, Issue 17
A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1
journal, May 2019
- Zhao, Baoyu; Du, Fenglei; Xu, Pengbiao
- Nature, Vol. 569, Issue 7758
Hydrolysis of 2′3′-cGAMP by ENPP1 and design of nonhydrolyzable analogs
journal, October 2014
- Li, Lingyin; Yin, Qian; Kuss, Pia
- Nature Chemical Biology, Vol. 10, Issue 12
Structural basis for SENP2 protease interactions with SUMO precursors and conjugated substrates
journal, November 2006
- Reverter, David; Lima, Christopher D.
- Nature Structural & Molecular Biology, Vol. 13, Issue 12
Extracellular cGAMP is a cancer-cell-produced immunotransmitter involved in radiation-induced anticancer immunity
journal, February 2020
- Carozza, Jacqueline A.; Böhnert, Volker; Nguyen, Khanh C.
- Nature Cancer, Vol. 1, Issue 2
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
Serine Protease Mechanism and Specificity
journal, December 2002
- Hedstrom, Lizbeth
- Chemical Reviews, Vol. 102, Issue 12
Transcriptional Responses of the Trichoplusia ni Midgut to Oral Infection by the Baculovirus Autographa californica Multiple Nucleopolyhedrovirus
journal, May 2019
- Shrestha, Anita; Bao, Kan; Chen, Wenbo
- Journal of Virology, Vol. 93, Issue 14
MAFFT Multiple Sequence Alignment Software Version 7: Improvements in Performance and Usability
journal, January 2013
- Katoh, K.; Standley, D. M.
- Molecular Biology and Evolution, Vol. 30, Issue 4
SLC19A1 Is an Importer of the Immunotransmitter cGAMP
journal, July 2019
- Ritchie, Christopher; Cordova, Anthony F.; Hess, Gaelen T.
- Molecular Cell, Vol. 75, Issue 2
Genetic mapping of non-target-site resistance to a sulfonylurea herbicide (Envoke®) in Upland cotton (Gossypium hirsutum L.)
journal, September 2013
- Thyssen, Gregory; McCarty, Jack C.; Li, Ping
- Molecular Breeding, Vol. 33, Issue 2
Structure-Function Analysis of STING Activation by c[G(2′,5′)pA(3′,5′)p] and Targeting by Antiviral DMXAA
journal, August 2013
- Gao, Pu; Ascano, Manuel; Zillinger, Thomas
- Cell, Vol. 154, Issue 4
Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance
journal, July 2018
- Zhou, Wen; Whiteley, Aaron T.; de Oliveira Mann, Carina C.
- Cell, Vol. 174, Issue 2
Structure-function insights into chikungunya virus capsid protein: Small molecules targeting capsid hydrophobic pocket
journal, February 2018
- Sharma, Rajesh; Kesari, Pooja; Kumar, Pravindra
- Virology, Vol. 515
Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High-Affinity Ligand for STING
journal, July 2013
- Zhang, Xu; Shi, Heping; Wu, Jiaxi
- Molecular Cell, Vol. 51, Issue 2
Deciphering the Virome of Culex vishnui Subgroup Mosquitoes, the Major Vectors of Japanese Encephalitis, in Japan
journal, February 2020
- Faizah, Astri Nur; Kobayashi, Daisuke; Isawa, Haruhiko
- Viruses, Vol. 12, Issue 3
Autophagy induction via STING trafficking is a primordial function of the cGAS pathway
journal, March 2019
- Gui, Xiang; Yang, Hui; Li, Tuo
- Nature, Vol. 567, Issue 7747
STING cyclic dinucleotide sensing originated in bacteria
journal, September 2020
- Morehouse, Benjamin R.; Govande, Apurva A.; Millman, Adi
- Nature, Vol. 586, Issue 7829
Inflammation-Induced, STING-Dependent Autophagy Restricts Zika Virus Infection in the Drosophila Brain
journal, July 2018
- Liu, Yuan; Gordesky-Gold, Beth; Leney-Greene, Michael
- Cell Host & Microbe, Vol. 24, Issue 1
Structure-Guided Reprogramming of Human cGAS Dinucleotide Linkage Specificity
journal, August 2014
- Kranzusch, Philip J.; Lee, Amy S. Y.; Wilson, Stephen C.
- Cell, Vol. 158, Issue 5
Gentian Kobu-sho-associated virus: a tentative, novel double-stranded RNA virus that is relevant to gentian Kobu-sho syndrome
journal, December 2012
- Kobayashi, Kappei; Atsumi, Go; Iwadate, Yasuya
- Journal of General Plant Pathology, Vol. 79, Issue 1
A Diverse Range of Novel RNA Viruses in Geographically Distinct Honey Bee Populations
journal, May 2017
- Remnant, Emily J.; Shi, Mang; Buchmann, Gabriele
- Journal of Virology, Vol. 91, Issue 16
A novel cypovirus found in a betabaculovirus co-infection context contains a poxvirus immune nuclease (poxin)-related gene
journal, June 2020
- Silva, Leonardo A. da; Ardisson-Araújo, Daniel M. P.; de Camargo, Brenda R.
- Journal of General Virology, Vol. 101, Issue 6
Polydnaviruses: From discovery to current insights
journal, May 2015
- Strand, Michael R.; Burke, Gaelen R.
- Virology, Vol. 479-480
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
Rates of evolutionary change in viruses: patterns and determinants
journal, March 2008
- Duffy, Siobain; Shackelton, Laura A.; Holmes, Edward C.
- Nature Reviews Genetics, Vol. 9, Issue 4
PROMALS3D: a tool for multiple protein sequence and structure alignments
journal, February 2008
- Pei, Jimin; Kim, Bong-Hyun; Grishin, Nick V.
- Nucleic Acids Research, Vol. 36, Issue 7
RNA-virus proteases counteracting host innate immunity
journal, September 2017
- Lei, Jian; Hilgenfeld, Rolf
- FEBS Letters, Vol. 591, Issue 20
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
Analysis of Drosophila STING Reveals an Evolutionarily Conserved Antimicrobial Function
journal, June 2018
- Martin, Marina; Hiroyasu, Aoi; Guzman, R. Marena
- Cell Reports, Vol. 23, Issue 12
Stimulator of interferon genes (STING) provides insect antiviral immunity by promoting Dredd caspase–mediated NF-κB activation
journal, June 2018
- Hua, Xiaoting; Li, Binbin; Song, Liang
- Journal of Biological Chemistry, Vol. 293, Issue 30
Benchmarking fold detection by DaliLite v.5
journal, July 2019
- Holm, Liisa
- Bioinformatics, Vol. 35, Issue 24
The Kinase IKKβ Regulates a STING- and NF-κB-Dependent Antiviral Response Pathway in Drosophila
journal, August 2018
- Goto, Akira; Okado, Kiyoshi; Martins, Nelson
- Immunity, Vol. 49, Issue 2
Prediction and Functional Analysis of Native Disorder in Proteins from the Three Kingdoms of Life
journal, March 2004
- Ward, J. J.; Sodhi, J. S.; McGuffin, L. J.
- Journal of Molecular Biology, Vol. 337, Issue 3
cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING
journal, May 2013
- Ablasser, Andrea; Goldeck, Marion; Cavlar, Taner
- Nature, Vol. 498, Issue 7454
Isolation and characterization of immune-related genes from the fall webworm, Hyphantria cunea, using PCR-based differential display and subtractive cloning
journal, November 1998
- Woon Shin, Sang; Park, Soon-Sik; Park, Doo-Sang
- Insect Biochemistry and Molecular Biology, Vol. 28, Issue 11
Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels Augments STING-Mediated Interferon Responses and Anti-viral Immunity
journal, May 2020
- Zhou, Chun; Chen, Xia; Planells-Cases, Rosa
- Immunity, Vol. 52, Issue 5
A novel virus from Macrosiphum euphorbiae with similarities to members of the family Flaviviridae
journal, May 2016
- Teixeira, Marcella; Sela, Noa; Ng, James
- Journal of General Virology, Vol. 97, Issue 5
Divergent Viruses Discovered in Arthropods and Vertebrates Revise the Evolutionary History of the Flaviviridae and Related Viruses
journal, October 2015
- Shi, Mang; Lin, Xian-Dan; Vasilakis, Nikos
- Journal of Virology, Vol. 90, Issue 2
The Schlafen family: complex roles in different cell types and virus replication: The characteristics and functions of Schlafen family
journal, June 2017
- Liu, Furao; Zhou, Pingting; Wang, Qian
- Cell Biology International, Vol. 42, Issue 1
Reciprocal-space solvent flattening
journal, November 1999
- Terwilliger, Thomas C.
- Acta Crystallographica Section D Biological Crystallography, Vol. 55, Issue 11
The evolutionary biology of poxviruses
journal, January 2010
- Hughes, Austin L.; Irausquin, Stephanie; Friedman, Robert
- Infection, Genetics and Evolution, Vol. 10, Issue 1
Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS–STING signalling
journal, February 2019
- Eaglesham, James B.; Pan, Youdong; Kupper, Thomas S.
- Nature, Vol. 566, Issue 7743
Structural basis of STING binding with and phosphorylation by TBK1
journal, March 2019
- Zhang, Conggang; Shang, Guijun; Gui, Xiang
- Nature, Vol. 567, Issue 7748