Many cytoplasmic substrates degraded by autophagy have been identified; however, the impact of RNA degradation by autophagy remains uncertain. Retrotransposons comprise 40% of the human genome and are a major source of genetic variation among species, individuals and cells. Retrotransposons replicate via a copy-paste mechanism involving a cytoplasmic RNA intermediate. Here we report that autophagy degrades retrotransposon RNA from both long and short interspersed elements, preventing new retrotransposon insertions into the genome. Retrotransposon RNA localizes to RNA granules, whose selective degradation is facilitated by the autophagy receptors NDP52 and p62. Accordingly, NDP52 and p62 control retrotransposon insertion in the genome. Mice lacking a copy of Atg6/Beclin1, a gene critical for autophagy, also accumulate both retrotransposon RNA and genomic insertions. Thus, autophagy physiologically buffers genetic variegation by degrading retrotransposon RNA. This may contribute to the increased tumorigenesis occuring when autophagy is inhibited and suggest a role for autophagy in tempering evolutionary change.
