A trove of antiviral TRIM family E3 ligases in reptiles

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.