Here we demonstrate that the putative RNA helicase MOV10 is a potent inhibitor of LINE1-mediated retrotransposition when overexpressed in cells. Conversely, knockdown of endogenous MOV10 results in a significant increase in levels of L1 retrotransposition. These results parallel the recently described capacity of MOV10 to diminish viral production and infectivity of HIV and other pathogenic retroviruses 
. Association with the L1 retrotransposition machinery is confirmed by markedly close colocalization of MOV10 protein with ORF1p in cytoplasmic granules, and by the detection of MOV10 in RNP particles retrieved by immunoprecipitation of tagged L1 constructs. The loss of RNP association upon RNase treatment suggests that MOV10 may bind the L1 RNA, as it is also known to associate with HIV RNA and to interact with Gag in an RNA-dependent manner 
. Affinity of MOV10 protein for the L1 RNP likely facilitates the inhibition of L1 expression that we observe in cell culture ().
The mechanism by which MOV10 inhibits retrotransposition remains unclear, but in light of MOV10 association with RISC, it is reasonable to consider that RNAi silencing is involved. Two studies have reported that L1-derived small (sm) RNAs participate in its inhibition 
, but failed to verify these as genuine siRNAs. The question of siRNA control of retrotransposition therefore remains open. Stronger evidence exists that components of the germline piRNA pathway mediate retrotransposon control. Significantly, the MOV10 paralog MOV10L binds piRNA-associated proteins MILI and MIWI, and MOV10L loss in testes of knockout mice is marked by an increase in IAP and L1 expression 
piRNAs appear to inhibit retrotransposons by stimulating de novo
methylation of their regulatory sequences 
. Loss of MILI, MIWI2, or GASZ impairs IAP and L1 promoter methylation, together with a reduction in repeat-associated piRNAs and derepression of retrotransposon transcription in germ cells of male newborn mice 
. Also, it was recently demonstrated in KO mice that loss of MVH (DDX4), an ATP-dependent RNA helicase, causes the same germ line abnormalities as loss of MILI and MIWI2, and similarly plays an essential role in de novo
methylation and silencing of retrotransposons 
. MVH is the homolog of Vasa, a Drosophila protein involved in piRNA production. It should be noted, however, that none of these KO mouse studies demonstrated that an increase in retrotransposon expression actually led to an increase in endogenous retrotransposition
As noted above, MOV10 localizes with AGO1 and AGO2 in stress granules and P-bodies 
, sites of translationally-silenced RNPs and mRNA decay, respectively 
. Likewise, ORF1p is found together with AGO2, and other components of RISC 
, and also closely associates with MOV10 in cytoplasmic granules. We propose that MOV10 is able to recruit L1 RNPs to stress granules (), so fating them for silencing and possible degradation by smRNA pathways. Nevertheless, evidence is conflicted for the role of cytoplasmic granules in retrotransposition. Studies to date have dealt with retroviral-like LTR elements and P-bodies only. P-body components are important for retrotransposition of yeast Ty3 retrotransposons 
. However, P-body disruption increases retrotransposition of mouse IAP elements 
. Considerably more work is required to elucidate the implications of granule targeting for non-LTR retrotransposition.
Of course, helicases are involved in many other cellular processes, including transcription, pre-mRNA processing, RNA export, translation, RNA storage, RNA decay, and ribosome biogenesis (reviewed in ref. 
). In turn, retrotransposition is a complex process involving transcription of the full-length L1, RNA transport to the cytoplasm, translation of the bicistronic RNA, formation of an RNP particle followed by its re-import to the nucleus, targeting of the genomic integration site, nicking the DNA bottom strand, priming and reverse transcription, second strand synthesis, and resolution of the integrant. Many mysteries remain concerning this process. At each of these steps helicases could play a role, either promoting or, as we have demonstrated for MOV10, inhibiting retrotransposition. In addition to MOV10, we detected five other RNA helicases associated with the L1 RNP. Compared with MOV10, the effects of their overexpression on cell culture retrotransposition are modest. However, we believe that more detailed investigation of these other helicases, including their knockdown in cells and mouse models, could prove fruitful.
It has been proposed that there is a genetic “arms race” with infecting retroviruses and endogenous retrotransposons, whereby the cell constantly evolves new means to counter infection or transposition. This places selective pressure on the parasitic element, which in turn contrives to evolve counter measures to evade repression 
. Primate lentiviruses, for example, encode an arsenal of accessory proteins designed to disable host immune factors. These proteins include Virion infectivity factor (Vif), Viral protein X (Vpx), and Viral protein U (Vpu) arrayed, respectively, against cell-encoded APOBEC3G, SAMHD1, and tetherin/BST-2 (summarized in 
). No viral antagonist of MOV10 has been reported.
One signature of the struggle between host and pathogen is positive selection for alleles that confer fitness benefit. To ascertain if MOV10 shows signs of positive selection, we determined the relative numbers of non-synonymous (dN) and synonymous (dS) nucleotide substitutions per site and dN/dS (ω) ratios over seven primate species using the PAML 4.5 software package 
. Positive selection would be supported by an excess of non-synonymous amino acid subsitutions (which alter amino acids) relative to synonymous subsitutions, i.e. ω>1. A phylogenic tree for the complete sequences of MOV10 homologs was constructed and ω ratios compared across the primate lineages (Figures S1
). No positive selection was predicted. This is surprising if MOV10 protein is engaged in a coevolutionary arms race with rapidly evolving retroviral proteins. However, strong sequence conservation across primate species is consistent with an essential biochemical role for MOV10. This role might be its function in the RISC complex, although in Drososphila at least, siRNA pathway genes are among the fastest evolving 
. Lack of positive selection is also expected if a significant function for MOV10 is protection of the genome from LINE1s, the only autonomous active endogenous retroelement. L1s are not rapidly generating new and active variants. Five L1 subfamilies have succeeded each other as a single lineage during the course of hominoid evolution, each replacing the last as the dominant active form 
. With the exception of a 217-nt long fragment of the coiled-coil domain of ORF1p that shows evidence for positive selection, Boissinot and Furano 
found strong L1 protein sequence conservation over long periods of time, mediated by clearing of deleterious elements from the genome and purifying selection. This has brought us to the point where, although over half a million defective L1s litter the genome, only about 80 to 100 are considered to be potentially active, most of these members of the youngest L1PA1 subfamily and highly conserved in sequence 
. If a primary combatant of retrotransposition, the trajectory of primate MOV10 evolution would be expected to fit a “trench warfare” or balancing selection model 
rather than arms race model, i.e. maintenance of the same beneficial alleles over long periods of time.
Phylogenetic analyses suggest that eukaryote non-LTR retrotransposons predate all LTR retrotransposons, which in turn gave rise to retroviruses through the acquisition of an envelope (env) gene 
. With homologs in worms, flies and plants, MOV10 is a member of an ancient subfamily of RNA helicases. Effective against invading retroviruses, MOV10-like proteins may have first evolved to guard the genome against an internal threat.