Sequestration of LINE‐1 in cytosolic aggregates by MOV10 restricts retrotransposition

Abstract

LINE-1 (L1) retroelements have retained their ability to mobilize. Mechanisms regulating L1 mobility include DNA methylation in somatic cells and the piRNA pathway in the germline. During preimplantation stages of mouse embryonic development, however, both pathways are inactivated leading to a window necessitating alternate means of L1 regulation. We previously reported an increase in L1 levels in Dicer_KO mouse embryonic stem cells (mESCs), which was accompanied by only a marginal increase in retrotransposition, suggesting additional mechanisms suppressing L1 mobility. Here, we demonstrate that L1 ribonucleoprotein complexes (L1 RNP) accumulate as aggregates in the cytoplasm of Dicer_KO mESCs along with the RNA helicase MOV10. The combined overexpression of L1 ORF1p and MOV10 is sufficient to create L1 RNP aggregates. In Dicer_KO mESCs, MOV10 is upregulated due to the loss of its direct regulation by miRNAs. The newly discovered posttranscriptional regulation of Mov10, and its role in preventing L1 retrotransposition by driving cytosolic aggregation, provides routes to explore for therapy in disease conditions where L1s are upregulated.

Nuclear translocation of LINE-1 encoded ORF1p alters nuclear envelope integrity and disrupts nucleocytoplasmic transport in human neurons

“…The small transcriptional increase in LINE-1 RNA following arsenite treatment suggests that the overall increase in ORF1p could be partially transcriptional and partially post-transcriptional, possibly by releasing LINE-1 RNA stored in P-bodies for translation 84,85 . Once ORF1p translocates to the nucleus, it accumulates at the inner NE by directly binding to Lamin B1 in a stress-specific manner.…”

Investigating the Evolution of Drosophila STING-Dependent Antiviral Innate Immunity by Multispecies Comparison of 2′3′-cGAMP Responses

“…Interestingly, these genes have been duplicated in a subset of species ( D. melanogaster , D. simulans , D. yakuba, and D. santomea ) and all but 1 paralog is up-regulated. Other candidates emerging from this comparative expression screen include CG17224 (a predicted uridine phosphorylase induced in 7/10 species), CG12129 (predicted role in transcription and RNA binding, induced in 6/10 species), CG6967 (a helicase related to the RNA induced silencing complex component (RISC) MOV10 ( Arora et al 2022 ; Liu et al 2023 ), induced in 6/10 species) and CG8353 (a predicted cytidine deaminase induced in 6/10 species). To test the antiviral activity of candidates, we constructed expression vectors for members of the HOGs 11838, 14240, 19556, and 11154, established stable cell lines and infected them with 3 viruses sensitive to the activation of the STING pathway, DCV, Vesicular Stomatitis Virus (VSV; Rhabdoviridae ) and Flock House Virus (FHV; Nodaviridae ) ( Fig.…”

ZCCHC3 is a stress granule zinc knuckle protein that strongly suppresses LINE-1 retrotransposition

“…The inhibitory action of ZCCHC3 is analogous in a number of ways to the retroelement inhibitory factors MOV10 DExD-box RNA helicase and ZAP zinc-finger protein. These host proteins are known to restrict viral infection in mammals and were shown by ourselves and others to reduce human cell culture retrotransposition by greater than 95 percent when overexpressed or to increase retrotransposition 2- to 3-fold when inhibited ( Fig 2E ) [ 28 – 32 , 64 ].…”