Sequestration of LINE-1 in novel cytosolic bodies by MOV10 restricts retrotransposition

Abstract

LINE-1 (L1) are autonomous retroelements that have retained their ability to mobilize. Mechanisms regulating L1 mobility include DNA methylation in somatic cells and the Piwi-interacting RNA pathway in the germline. During pre-implantation stages of mouse embryonic development, however, both pathways are inactivated leading to a critical window necessitating alternate means of L1 regulation. We previously reported an increase in L1 levels in Dicer_KO mouse embryonic stem cells (mESCs). Intriguingly this was accompanied by only a marginal increase in retrotransposition, suggestive of additional mechanisms suppressing L1 mobility. Here, we demonstrate that L1 Ribonucleoprotein complexes (L1 RNP) accumulate as aggregates in Dicer_KO cytoplasm along with the RNA helicase MOV10. The combined overexpression of L1 RNAs and MOV10 is sufficient to create L1 RNP aggregates in stem cells. In Dicer_KO mESCs, MOV10 is upregulated due to the loss of its direct regulation by miRNAs. The newly discovered post-transcriptional regulation of Mov10 expression, and its role in preventing L1 retrotransposition by driving novel cytosolic aggregation affords alternate routes to explore for therapy and disease progression.

The MOV10 RNA helicase is a dosage-dependent host restriction factor for LINE1 retrotransposition in mice

“…Loss of MOV10 caused upregulation of two L1 families but did not change the overall level of L1 transcripts in mouse testis. In addition, MOV10 sequesters L1 ribonucleoprotein particles in the cytosolic aggregates [55]. Second, MOV10 interacts with L1-encoded ORF2 and recombinant MOV10 blocks reverse transcription in vitro [51].…”

An update on post‐transcriptional regulation of retrotransposons

“…We further showed that TUT, and, to a much lesser extent, TUT7 interact in an RNAdependent manner with MOV10, which is a 5 0 ? 3 0 helicase binding to the LINE-1 mRNA 3 0 ends [154] and a known virus and retrotransposon restriction factor [155][156][157][158][159][160][161][162]. In fact, further in vitro biochemical and in vivo cross-linking assays confirmed that MOV10 can traverse along the LINE-1 3' UTR sequence displacing the bound proteins (L1-ORF1p) and likely setting the stage for uridylation [65].…”

“…LINE-1 RNPs aggregate in cytoplasm-forming foci, which I propose calling LINE-1 bodies, often colocalizing with endogenous proteins markers of stress granules, P-bodies or even virus-like particles [48,65,[171][172][173][174]. Recently, sequestration of LINE-1 RNPs in cytoplasmic bodies comprising MOV10 and enhanced by MOV10 overexpression was suggested as a mechanism of LINE-1 retrotransposition restriction in DICER KO mouse ESCs [162]. Another study showed the sequestration of LINE-1 RNPs to stress granules upon HCV infection and linked this with reduced retrotransposition [175].…”

“…Curiously, while for APOBEC3A, the cytidine deaminase activity is necessary for LINE-1 restriction [216], it was dispensable in the case of APOBECB, C and F [229,232,240]. Another wellestablished restriction factor is the already mentioned MOV10 [65,[155][156][157][158][159][160][161][162]210]. Basal but easily detectable expression of the MOV10 gene is further induced by interferon.…”

“…By using reporters with specially designed 3′ ends of validated sequence, we demonstrated that even a single 3′ uridine reduces retrotransposition potential by one‐fourth of the control levels [65]. We further showed that TUT, and, to a much lesser extent, TUT7 interact in an RNA‐dependent manner with MOV10, which is a 5′ → 3′ helicase binding to the LINE‐1 mRNA 3′ ends [154] and a known virus and retrotransposon restriction factor [155–162]. In fact, further in vitro biochemical and in vivo cross‐linking assays confirmed that MOV10 can traverse along the LINE‐1 3' UTR sequence displacing the bound proteins (L1‐ORF1p) and likely setting the stage for uridylation [65].…”