Figure 6.

Activation of retrotransposons induces immune responses. TE expression can result in the generation of cytosolic nucleic acids that can induce a type I interferon response via multiple mechanisms—processes termed viral mimicry. For example, TE RNA transcripts, including Alu, ERVs, and LINE-1, have the potential to generate double-stranded RNAs via intramolecular or intermolecular base pairing, which could be sensed by MDA5 and RIG-I to elicit an innate immune response. In addition, DNA-damaging effects of ORF2p EN or cDNA products of ORF2p RT activity could be sources for cytosolic double-stranded DNAs or DNA–RNA hybrids, which could be sensed by cGAS–STING to elicit an innate immune response. Moreover, TE-derived neoantigens could elicit an adaptive immune response, which could be generated via translation of peptides encoded by ERV transcripts containing partially intact ORFs or ORF0 chimeric transcripts generated via aberrant splicing of LINE-1 copies with nearby genes.