Boys Ian N, Quinlan Meghan R, 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. 2025 Jun 25:2025.06.23.661133. doi: 10.1101/2025.06.23.661133.
Many scaled reptiles (squamates) are exposed to flaviviruses but some, including iguanas, exhibit strong resistance to infection. To identify genes encoding viral resistance, we screened a cDNA library generated from green iguana and discovered a reptilian TRIM-family E3 ubiquitin ligase that reduces dengue virus replication ~10,000-fold. Experimental evolution identified flavivirus capsid as the substrate of this ligase, revealing an apparent evolutionary vulnerability for flaviviruses, which depend on capsid ubiquitylation to infect cells. HarbingerTRIM is situated in a cluster of related genes near an intact transposable element in squamate genomes. Analysis of a sampling of harbiTRIM variants among reptile species revealed distinct antiviral properties, highlighting the vast potential of querying diverse animal genomes for discovering new defenses to pandemic viruses.
许多有鳞目爬行动物（蜥蜴亚目）会接触到黄病毒，但包括鬣蜥在内的一些物种对感染表现出很强的抵抗力。为了鉴定编码病毒抗性的基因，我们筛选了从绿鬣蜥构建的cDNA文库，并发现了一种爬行类TRIM家族E3泛素连接酶，它能将登革病毒的复制减少约10000倍。实验进化确定黄病毒衣壳是这种连接酶的底物，揭示了黄病毒明显的进化弱点，黄病毒依赖衣壳泛素化来感染细胞。先驱TRIM位于蜥蜴亚目基因组中一个完整转座元件附近的一组相关基因中。对爬行动物种群中先驱TRIM变体样本的分析揭示了不同的抗病毒特性，突出了通过查询不同动物基因组来发现针对大流行病毒新防御机制的巨大潜力。
