AGO2 slicing of a domesticated retrotransposon is necessary for normal vasculature development
Argonaute-mediated RNA slicing is an ancient genome-defense mechanism linked to transposon repression. Although RNAi is no longer a major repeat-control pathway in mammals, AGO2 has retained catalytic activity, and this activity is essential for postnatal viability. The physiological targets that explain this requirement have remained unknown. Here we show that mammalian AGO2 slicing is required to restrain Rtl1, an imprinted domesticated retrotransposon whose cleavage is directed by miRNAs from the miR-433[~]127 cluster. Loss of AGO2 catalysis derepresses Rtl1 and causes endothelial defects and lethal neonatal muscle failure. Mechanistically, RTL1 is an oligomerization-prone retrotransposon-derived protein whose excess expression in muscle induces a non-aggregate proteostasis-stress state characterized by increased proteasome-dependent activity, reduced nascent protein synthesis, and depletion of mitochondrial, calcium-handling, and contractile gene programs. Thus, an essential function of mammalian AGO2 catalysis is to restrain a domesticated transposon-derived protein whose uncontrolled expression compromises endothelial and skeletal muscle function. These findings reveal how an ancestral transposon-Argonaute regulatory interaction has been repurposed to support mammalian development and survival.