Human TRIM5α senses and restricts LINE-1 elements

Mobile genetic elements have significantly shaped our genomic landscape. LINE-1 retroelements are the only autonomously active elements left in the human genome. Since new insertions can have detrimental consequences, cells need to efficiently control LINE-1 retrotransposition. Here, we demonstrate that the intrinsic immune factor TRIM5 alpha senses and restricts LINE-1 retroelements. Previously, rhesus TRIM5 alpha has been shown to efficiently block HIV-1 replication, while human TRIM5 alpha was found to be less active. Surprisingly, we found that both human and rhesus TRIM5 alpha efficiently repress human LINE-1 retrotransposition. TRIM5 alpha interacts with LINE-1 ribonucleoprotein complexes in the cytoplasm, which is essential for restriction. In line with its postulated role as pattern recognition receptor, we show that TRIM5 alpha also induces innate immune signaling upon interaction with LINE-1 ribonucleoprotein complexes. The signaling events activate the transcription factors AP-1 and NF-kappa B, leading to the down-regulation of LINE-1 promoter activity. Together, our findings identify LINE-1 as important target of human TRIM5 alpha, which restricts and senses LINE-1 via two distinct mechanisms. Our results corroborate TRIM5 alpha as pattern recognition receptor and shed light on its previously undescribed activity against mobile genetic elements, such as LINE-1, to protect the integrity of our genome.