Abstract
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 Harbinger 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.