Boys Ian N, Johnson Alex G, Quinlan Meghan, Kranzusch Philip J, Elde Nels C
Department of Human Genetics, University of Utah, Salt Lake City, Utah, 84112 USA.
Howard Hughes Medical Institute, Chevy Chase, Maryland, 20815, USA.
bioRxiv. 2023 Apr 3:2023.02.26.529821. doi: 10.1101/2023.02.26.529821.
Viruses acquire host genes via horizontal gene transfer and can express them to manipulate host biology during infections. Some viral and host homologs retain sequence identity, but evolutionary divergence can obscure host origins. We used structural modeling to compare vaccinia virus proteins with metazoan proteomes. We identified vaccinia as a homolog of gasdermins, the executioners of pyroptosis. An X-ray crystal structure of A47 confirmed this homology and cell-based assays revealed that A47 inhibits pyroptosis. We also identified vaccinia 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 a benefit to poxvirus replication in some circumstances. Our findings demonstrate the potential of structural homology screens to reveal genes that viruses capture from hosts and repurpose to benefit viral fitness.
病毒通过水平基因转移获取宿主基因，并在感染过程中表达这些基因以操纵宿主生物学特性。一些病毒和宿主同源物保留了序列同一性，但进化分歧可能会掩盖宿主起源。我们使用结构建模将痘苗病毒蛋白与后生动物蛋白质组进行比较。我们确定痘苗病毒是焦亡执行者gasdermin的同源物。A47的X射线晶体结构证实了这种同源性，基于细胞的实验表明A47抑制焦亡。我们还确定痘苗病毒是一个隐秘基因融合事件的产物，该事件将Bcl-2相关折叠与pyrin结构域结合在一起。C1与炎性小体的成分相关联，炎性小体是一种参与焦亡的胞质固有免疫传感器，但矛盾的是它会增强炎性小体的活性，这表明在某些情况下对痘病毒复制有益。我们的研究结果证明了结构同源性筛选在揭示病毒从宿主捕获并重新利用以利于病毒适应性的基因方面的潜力。
