Abstract
MOV10 protein, a putative RNA helicase and component of the RNA–induced silencing complex (RISC), inhibits retrovirus replication. We show that MOV10 also severely restricts human LINE1 (L1), Alu, and SVA retrotransposons. MOV10 associates with the L1 ribonucleoprotein particle, along with other RNA helicases including DDX5, DHX9, DDX17, DDX21, and DDX39A. However, unlike MOV10, these other helicases do not strongly inhibit retrotransposition, an activity dependent upon intact helicase domains. MOV10 association with retrotransposons is further supported by its colocalization with L1 ORF1 protein in stress granules, by cytoplasmic structures associated with RNA silencing, and by the ability of MOV10 to reduce endogenous and ectopic L1 expression. The majority of the human genome is repetitive DNA, most of which is the detritus of millions of years of accumulated retrotransposition. Retrotransposons remain active mutagens, and their insertion can disrupt gene function. Therefore, the host has evolved defense mechanisms to protect against retrotransposition, an arsenal we are only beginning to understand. With homologs in other vertebrates, insects, and plants, MOV10 may represent an ancient and innate form of immunity against both infective viruses and endogenous retroelements.
Highlights
MOV10 was originally identified as a protein that prevents infection of mice by Moloney murine leukemia virus [1,2], and has been classified as a member of the UPF1p family of SF-1 ATP-dependent RNA helicases [3,4,5,6]
MOV10 is a homolog of SDE3, a helicase necessary for post-transcriptional gene silencing in Arabidopsis, armitage, a protein involved in RNA–induced silencing complex (RISC) assembly and piRNA control of doublestrand RNA viruses and endogenous retroelements in Drosophila, and ERI-6/7, which acts with Argonaute protein ERGO-1 to generate specific subsets of siRNAs in Caenorhabditis elegans [6,7,8,9]
We demonstrate that the putative RNA helicase MOV10, recently discovered to limit production and infectivity of retroviruses, profoundly inhibits retrotransposition of L1s, Alus, and SVAs in cell culture
Summary
MOV10 was originally identified as a protein that prevents infection of mice by Moloney murine leukemia virus [1,2], and has been classified as a member of the UPF1p family of SF-1 ATP-dependent RNA helicases [3,4,5,6]. MOV10 is a homolog of SDE3, a helicase necessary for post-transcriptional gene silencing in Arabidopsis, armitage, a protein involved in RISC assembly and piRNA control of doublestrand RNA viruses and endogenous retroelements in Drosophila, and ERI-6/7, which acts with Argonaute protein ERGO-1 to generate specific subsets of siRNAs in Caenorhabditis elegans [6,7,8,9]. The 1003-amino acid MOV10 (Figure S1) is present in a multi-protein complex with RISC components HIV-1 TAR RNA-binding protein (TRBP) and eukaryotic translation initiation factor 6 (eIF6). Members of the APOBEC3 family of cytosine deaminases were originally defined by their ability to hypermutate reverse transcripts of human immunodeficiency virus (HIV) RNA, and subsequently were found to inhibit retrotransposition of endogenous retroelements by a poorly defined process that does not appear to involve deamination of cDNA Members of the APOBEC3 family of cytosine deaminases were originally defined by their ability to hypermutate reverse transcripts of human immunodeficiency virus (HIV) RNA, and subsequently were found to inhibit retrotransposition of endogenous retroelements by a poorly defined process that does not appear to involve deamination of cDNA (reviewed in refs. [14,15])
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