{"title":"piRNA Defense Against Endogenous Retroviruses.","authors":"Milky Abajorga, Leonid Yurkovetskiy, Jeremy Luban","doi":"10.3390/v16111756","DOIUrl":null,"url":null,"abstract":"<p><p>Infection by retroviruses and the mobilization of transposable elements cause DNA damage that can be catastrophic for a cell. If the cell survives, the mutations generated by retrotransposition may confer a selective advantage, although, more commonly, the effect of new integrants is neutral or detrimental. If retrotransposition occurs in gametes or in the early embryo, it introduces genetic modifications that can be transmitted to the progeny and may become fixed in the germline of that species. PIWI-interacting RNAs (piRNAs) are single-stranded, 21-35 nucleotide RNAs generated by the PIWI clade of Argonaute proteins that maintain the integrity of the animal germline by silencing transposons. The sequence specific manner by which piRNAs and germline-encoded PIWI proteins repress transposons is reminiscent of CRISPR, which retains memory for invading pathogen sequences. piRNAs are processed preferentially from the unspliced transcripts of piRNA clusters. Via complementary base pairing, mature antisense piRNAs guide the PIWI clade of Argonaute proteins to transposon RNAs for degradation. Moreover, these piRNA-loaded PIWI proteins are imported into the nucleus to modulate the co-transcriptional repression of transposons by initiating histone and DNA methylation. How retroviruses that invade germ cells are first recognized as foreign by the piRNA machinery, as well as how endogenous piRNA clusters targeting the sequences of invasive genetic elements are acquired, is not known. Currently, koalas (<i>Phascolarctos cinereus)</i> are going through an epidemic due to the horizontal and vertical transmission of the KoRV-A gammaretrovirus. This provides an unprecedented opportunity to study how an exogenous retrovirus becomes fixed in the genome of its host, and how piRNAs targeting this retrovirus are generated in germ cells of the infected animal. Initial experiments have shown that the unspliced transcript from KoRV-A proviruses in koala testes, but not the spliced KoRV-A transcript, is directly processed into sense-strand piRNAs. The cleavage of unspliced sense-strand transcripts is thought to serve as an initial innate defense until antisense piRNAs are generated and an adaptive KoRV-A-specific genome immune response is established. Further research is expected to determine how the piRNA machinery recognizes a new foreign genetic invader, how it distinguishes between spliced and unspliced transcripts, and how a mature genome immune response is established, with both sense and antisense piRNAs and the methylation of histones and DNA at the provirus promoter.</p>","PeriodicalId":49328,"journal":{"name":"Viruses-Basel","volume":"16 11","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11599104/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Viruses-Basel","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/v16111756","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"VIROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Infection by retroviruses and the mobilization of transposable elements cause DNA damage that can be catastrophic for a cell. If the cell survives, the mutations generated by retrotransposition may confer a selective advantage, although, more commonly, the effect of new integrants is neutral or detrimental. If retrotransposition occurs in gametes or in the early embryo, it introduces genetic modifications that can be transmitted to the progeny and may become fixed in the germline of that species. PIWI-interacting RNAs (piRNAs) are single-stranded, 21-35 nucleotide RNAs generated by the PIWI clade of Argonaute proteins that maintain the integrity of the animal germline by silencing transposons. The sequence specific manner by which piRNAs and germline-encoded PIWI proteins repress transposons is reminiscent of CRISPR, which retains memory for invading pathogen sequences. piRNAs are processed preferentially from the unspliced transcripts of piRNA clusters. Via complementary base pairing, mature antisense piRNAs guide the PIWI clade of Argonaute proteins to transposon RNAs for degradation. Moreover, these piRNA-loaded PIWI proteins are imported into the nucleus to modulate the co-transcriptional repression of transposons by initiating histone and DNA methylation. How retroviruses that invade germ cells are first recognized as foreign by the piRNA machinery, as well as how endogenous piRNA clusters targeting the sequences of invasive genetic elements are acquired, is not known. Currently, koalas (Phascolarctos cinereus) are going through an epidemic due to the horizontal and vertical transmission of the KoRV-A gammaretrovirus. This provides an unprecedented opportunity to study how an exogenous retrovirus becomes fixed in the genome of its host, and how piRNAs targeting this retrovirus are generated in germ cells of the infected animal. Initial experiments have shown that the unspliced transcript from KoRV-A proviruses in koala testes, but not the spliced KoRV-A transcript, is directly processed into sense-strand piRNAs. The cleavage of unspliced sense-strand transcripts is thought to serve as an initial innate defense until antisense piRNAs are generated and an adaptive KoRV-A-specific genome immune response is established. Further research is expected to determine how the piRNA machinery recognizes a new foreign genetic invader, how it distinguishes between spliced and unspliced transcripts, and how a mature genome immune response is established, with both sense and antisense piRNAs and the methylation of histones and DNA at the provirus promoter.
期刊介绍:
Viruses (ISSN 1999-4915) is an open access journal which provides an advanced forum for studies of viruses. It publishes reviews, regular research papers, communications, conference reports and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. We also encourage the publication of timely reviews and commentaries on topics of interest to the virology community and feature highlights from the virology literature in the ''News and Views'' section. Electronic files or software regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material.