Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity
Summary: 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 pro...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723008896 |
| _version_ | 1797731089934974976 |
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| author | Ian N. Boys Alex G. Johnson Meghan R. Quinlan Philip J. Kranzusch Nels C. Elde |
| author_facet | Ian N. Boys Alex G. Johnson Meghan R. Quinlan Philip J. Kranzusch Nels C. Elde |
| author_sort | Ian N. Boys |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-12T11:53:44Z |
| format | Article |
| id | doaj.art-6a30724b42384be2bec30172afec91c5 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T11:53:44Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-6a30724b42384be2bec30172afec91c52023-08-31T05:02:00ZengElsevierCell Reports2211-12472023-08-01428112878Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activityIan N. Boys0Alex G. Johnson1Meghan R. Quinlan2Philip J. Kranzusch3Nels C. Elde4Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USADepartment of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USADepartment of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USADepartment of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USADepartment of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723008896CP: MicrobiologyCP: Immunology |
| spellingShingle | Ian N. Boys Alex G. Johnson Meghan R. Quinlan Philip J. Kranzusch Nels C. Elde Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity Cell Reports CP: Microbiology CP: Immunology |
| title | Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity |
| title_full | Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity |
| title_fullStr | Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity |
| title_full_unstemmed | Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity |
| title_short | Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity |
| title_sort | structural homology screens reveal host derived poxvirus protein families impacting inflammasome activity |
| topic | CP: Microbiology CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723008896 |
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