Abstract Transposable elements can cause catastrophic genomic instability and are tightly regulated by the host through multiple restriction pathways. Domesticated elements are derived from these ancestors and have evolved adaptive roles but may retain pathological activity. For example, PEG10 is required for placentation but also promotes cancer and neurodegeneration. While much of PEG10 remains poorly understood, a unique feature is its ability to readily form virus-like particles (VLPs) which may contribute to its adaptive and pathological nature. However, comparable restriction networks that antagonize the harmful potential of domesticated genes like PEG10 remain unknown. Here, we describe restriction of PEG10 VLP abundance via UBQLN2 and the domesticated retrotransposon RTL8 . The gag-like RTL8 antagonizes PEG10 through competitive incorporation into VLPs reminiscent of transposable element inhibitors from diverse eukaryotes. These results represent the first known instance of a retroelement-derived restriction factor antagonizing another domesticated retrotransposon and have implications for our understanding of PEG10 biology.

The gag-like geneRTL8antagonizes PEG10-mediated virus like particles in humans