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Cited by 23Poxvirus research and outbreaksInflammasome and immune disordersinterferon and immune responses

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Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity

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Boys, Ian N., Johnson, Alex G., Quinlan, Meghan R., Kranzusch, Philip J., Elde, Nels C.·2023·Cell Reports
DOI 10.1016/j.celrep.2023.112878PMC PMC10715236

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Abstract

Viruses acquire host genes via horizontal transfer and can express them to manipulate host biology during infections. Some homologs retain sequence identity, but evolutionary divergence can obscure host origins. We use structural modeling to compare vaccinia virus proteins with metazoan proteomes. We identify vaccinia A47L as a homolog of gasdermins, the executioners of pyroptosis. An X-ray crystal structure of A47 confirms this homology, and cell-based assays reveal that A47 interferes with caspase function. We also identify vaccinia C1L as the product of a cryptic gene fusion event coupling a Bcl-2-related fold with a pyrin domain. C1 associates with components of the inflammasome, a cytosolic innate immune sensor involved in pyroptosis, yet paradoxically enhances inflammasome activity, suggesting differential modulation during infections. Our findings demonstrate the increasing power of structural homology screens to reveal proteins with unique combinations of domains that viruses capture from host genes and combine in unique ways.

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Metadata

Authors
Boys, I. N., Johnson, A. G., Quinlan, M. R., Kranzusch, P. J., & Elde, N. C.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Harvard University (US)
Corresponding author
Elde, Nels C.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2023-08
Volume
42
Issue
8
Pages
112878
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2023.112878
PMC
PMC10715236
OpenAlex
W4385252366
Cited by
23
References
7
Citations by year
2026: 7 · 2025: 3 · 2024: 12 · 2023: 1
FWCI
3.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Burroughs Wellcome Fund
  • University of Utah
  • Life Sciences Research Foundation
  • G. Harold and Leila Y. Mathers Foundation
  • Open Philanthropy Project
  • National Institutes of Health
  • Center for High Performance Computing
  • National Cancer Institute (R01CA260414)
  • National Institute of General Medical Sciences (R35GM134936)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › Poxvirus research and outbreaks
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
vaccinia virus, pyroptosis, inflammasome, caspase inhibition, horizontal gene transfer, pyrin domain, innate immunity

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