# Maximal inhibitory effect of MOV10 on LINE-1 retrotransposition requires both the MOV10/LINE-1 association and granule formation

## TL;DR

This study shows that MOV10 inhibits LINE-1 activity by interacting with it and forming granules, revealing how this process works in detail.

## Contribution

The study identifies specific MOV10 domains required for LINE-1 inhibition and granule formation.

## Key findings

- The 563-675aa domain of MOV10 interacts with LINE-1 to mediate its inhibition.
- The 907-1003aa domain is essential for granule formation, which enhances LINE-1 suppression.
- Both domains are necessary for maximal anti-LINE-1 activity by MOV10.

## Abstract

LINE-1 is the only active autonomous mobile element in the human, and its mobilization is tightly restricted by the host to maintain genetic stability. We recently reported that human MOV10 recruits DCP2 to decap LINE-1 RNA by liquid-liquid phase separation (LLPS), resulting in the inhibition of LINE-1 retrotransposition, while the detailed mechanism still awaits further exploration. In this report, we found that the extended motif II (563-675aa) and the C-terminal domain (907-1003aa) of MOV10 cooperated to achieve maximal inhibition on LINE-1 retrotransposition. The extended motif II involves the interaction between MOV10 and LINE-1, and the C-terminal domain is required for MOV10’s association with G3BP1 and thereby the formation of granules. The association with LINE-1 through the extended motif II is dominantly attributed to MOV10-mediated anti-LINE-1 activity. On this basis, promoting large granules formation by the C-terminal domain warrants maximal inhibition of LINE-1 replication by MOV10. These data together shed light on the detailed mechanism underlying MOV10-mediated inhibition of LINE-1 retrotransposition, and provide further evidence supporting the important role of MOV10-driven granules in the anti-LINE-1 action.

Transposons, often referred to as mobile or jumping genes, are DNA sequences capable of replicating and integrating into various chromosomal locations, accounting for up to 56% of the human genome. Among these, LINE-1 (Long Interspersed Nuclear Element-1) stands out as the only autonomously active transposon in humans, with its activation being closely associated with the onset of numerous diseases. Consequently, the host tightly regulates its activity. In prior research, we demonstrated that the host factor MOV10 facilitates the degradation of LINE-1 RNA by recruiting the decapping enzyme DCP2 and forming phase-separated structures. Building on these findings, we have now pinpointed the critical domains within MOV10 essential for this function: 563-675aa and 907-1003aa. Our results reveal that the 563-675aa domain is responsible for mediating interactions with the LINE-1 ribonucleoprotein (RNP) complex, whereas the 907–1003aa domain plays a crucial role in granule formation. In conclusion, our results reveal that the anti-LINE-1 activity of MOV10 is contingent upon its interaction with the LINE-1 ribonucleoprotein (RNP) complex and its capacity to assemble cytoplasmic granules.