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

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 modula-tion 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.

Automated summary

Viruses can acquire host genes through horizontal transfer and use them to manipulate host biology during infections. In this study, structural homology modeling was used to compare vaccinia virus proteins with metazoan proteomes. The researchers identified a homolog of gasdermins, proteins involved in cell death, as well as a fusion protein combining a Bcl-2-related fold with a pyrin domain. These findings highlight the power of structural homology screens in uncovering unique protein combinations captured by viruses from host genes.