This article was downloaded by: [The University of Edinburgh] On: 19 July 2015, At: 13:08 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: 5 Howick Place, London, SW1P 1WG RNA Biology Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/krnb20 RNA-mediated degradation of microRNAs: A widespread viral strategy? Jana McCaskillab, Pairoa Praihirunkitab, Paul M Sharpbc & Amy H Buckab a Institute of Immunology and Infection Research; School of Biological Sciences; University of Edinburgh; Edinburgh, UK b Centre for Immunity, Infection, and Evolution; University of Edinburgh; Edinburgh, UK c Institute of Evolutionary Biology; School of Biological Sciences; University of Edinburgh; Edinburgh, UK Accepted author version posted online: 07 Apr 2015. Click for updates To cite this article: Jana McCaskill, Pairoa Praihirunkit, Paul M Sharp & Amy H Buck (2015) RNA-mediated degradation of microRNAs: A widespread viral strategy?, RNA Biology, 12:6, 579-585, DOI: 10.1080/15476286.2015.1034912 To link to this article: http://dx.doi.org/10.1080/15476286.2015.1034912 PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. 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Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions POINT-OF-VIEW RNA Biology 12:6, 579--585; June 2015; © 2015 Taylor & Francis Group, LLC RNA-mediated degradation of microRNAs: A widespread viral strategy? y y Jana McCaskill1,2, , Pairoa Praihirunkit1,2, , Paul M Sharp2,3, and Amy H Buck1,2,* 1Institute of Immunology and Infection Research; School of Biological Sciences; University of Edinburgh; Edinburgh, UK; 2Centre for Immunity, Infection, and Evolution; University of Edinburgh; Edinburgh, UK; 3Institute of Evolutionary Biology; School of Biological Sciences; University of Edinburgh; Edinburgh, UK y These authors equally contributed to this work. egulation of small RNAs by other known to include, in some viral families, Rnon-coding RNAs is a ubiquitous the use of viral-encoded microRNAs feature of gene regulatory systems that (miRNAs) or viral-encoded miRNA can be exploited by viruses. Examples of inhibitors.1 miRNAs are a class of small this have been described in 3 different non-coding RNA that post-transcription- herpesviruses, where viral non-coding ally regulate gene expression. They derive RNAs bind to highly abundant cellular from stem loop structures generally con- (miRNAs), mediating their degradation: tained within Pol II transcripts, which are miR-27 is targeted by both murine cyto- recognized and processed by RNase III megalovirus and herpesvirus saimiri, enzymes in the nucleus (Drosha) and the while the miR-17 family is targeted by cytoplasm (Dicer), yielding a short dou- human cytomegalovirus. We review what ble-stranded RNA duplex, on average is known about RNA-mediated regula- 22 nt long. The duplex RNA is trans- tion of miRNA stability and propose 3 ferred to an Argonaute (Ago) protein in potential roles that viral non-coding the RNA-induced silencing complex RNAs might assume to initiate the (RISC) and one strand, the functional destruction of a miRNA, acting as miRNA, is selectively maintained whereas “recruiters,” “localizers” or “exposers.” the other “passenger” strand dissociates Whereas the miRNAs (miR-17 and miR- and is degraded (reviewed in2). The 27) appear to be ancient and pre-date the mature miRNA then guides RISC to spe- common ancestor of all mammalian her- cific mRNAs through base pair recogni- pesviruses, comparative analyses of her- tion, resulting in inhibited translation pesvirus genomes indicate that the 3 and/or accelerated de-adenylation of the known viral regulators of miRNA each mRNA.3 Specificity is largely dictated by evolved independently, and much more perfect complementarity between the tar- Downloaded by [The University of Edinburgh] at 13:08 19 July 2015 recently. Noting that the anti-viral activ- get and nucleotides 2–8 of the miRNA, ity of miRNAs might be countered by a termed the “seed site.”4 An individual variety of mechanisms, we propose that miRNA can therefore interact with hun- (i) there has been continual turnover of dreds of different mRNA targets and these mechanisms during herpesvirus indeed the majority of human protein- evolution, and (ii) there may be many coding genes contain miRNA-binding other, as yet undescribed, anti-miRNA sites retained under selective pressure.5 Keywords: herpesvirus, IL-10, micro- activities encoded by other herpesviruses Some viral transcripts also contain func- RNA, microRNA turnover, miRNA and indeed by viruses from other tional binding sites for host or virus- response element, RNA degradation, families. derived miRNAs. Therefore four different RNAi, viral evolution classes of miRNA-target interaction can *Correspondence to: Amy H Buck; impact the outcome of an infection: host- Email: [email protected] Introduction host, host-virus, virus-host or virus-virus. Submitted: 03/12/2015 There is extensive diversity in the func- Viruses use diverse mechanisms to tions of interactions in each class, depend- Revised: 03/18/2015 manipulate cellular gene expression ing on the miRNA, the target, the cell Accepted: 03/18/2015 toward conditions that are conducive to type, and the stage in the viral life cycle – http://dx.doi.org/10.1080/15476286.2015.1034912 replication or persistence and this is reviewed and referenced in depth www.tandfonline.com RNA Biology 579 elsewhere.6-8 Here our aim is to consider cytomegalovirus (MCMV), resulting in do not. Most known targets of miRNAs the mechanism and potential breadth of >90% reduction by 24 hours post-infec- are considered to be non-destructive but one specific mode of host miRNA-virus tion.17 This observation was intriguing could out-compete other targets depend- interaction, where targeting works in the because the half-lives of most miRNAs are ing on concentration, number of binding opposite direction and the viral RNA reported to be in the range of days18.We sites and affinity, according to studies of causes the degradation of the cellular and others subsequently identified an ceRNAs.26–28 On the other hand, it is not miRNA to which it binds. MCMV transcript that directly associates clear what factors make some RNAs with mature miR-27 and mediates its deg- destructive. From a theoretical standpoint, Widespread RNA-mediated radation.19,20 The miR-27 binding site is there are several modes by which RNAs regulation of small RNAs within the 30 UTR of the m169 gene and could mediate degradation of a miRNA: Regulation of miRNAs by other RNAs mutation of this binding site results in 1) they could specifically recruit proteins was first seen and coined “target mimicry” virus attenuation following in vivo infec- to the RNA that are required for turnover, in plants, where a non-coding RNA tion.20 Also in 2010, a distantly related including exonucleases; 2) they could induced during phosphate starvation herpesvirus from squirrel monkeys, Her- mediate localization of the miRNA to sites binds to miR-399 and relieves the repres- pesvirus saimiri (HVS), was shown to pro- associated with turnover or export; or 3) sion of its target, a phosphate storage regu- duce a small non-coding RNA, termed they could induce a conformational lator.9 A similar phenomenon occurs in HSUR-1, which binds to the same cellular change in the miRNA-RISC complex that bacteria where mRNAs and non-coding miRNA, and also mediates its degrada- exposes the miRNA, making it susceptible RNAs induced in response to environ- tion;21 this is thought to be involved in to modification and degradation by pro- mental cues bind to, and inhibit, small activation and potentially transformation teins. These modes of regulation are not RNAs that regulate sugar metabolism.10,11 of T-cells. Intriguingly, HSUR-1 and the mutually exclusive, however it is envi- Seitz postulated that competition between m169 30 UTR share no sequence similar- sioned that specific RNA motifs outside miRNA targets likely occurs naturally in ity, except in the short miR-27 binding the miRNA binding site would define a cells and might explain why some targets site. More recently, human cytomegalovi- “recruiter” or “localizer.” The concept of a do not appear important in physiological rus (HCMV) has been shown to produce recruiter seems logical given the presence assays: they have evolved miRNA-binding a non-coding RNA that binds to members of motifs in mRNAs that are associated sites so that they can regulate the miRNA, of a different miRNA family, miR-17, with mRNA stability and HSUR-1 is rather than to be regulated by the causing their degradation. Five of the degraded by an AU-rich element (ARE)- miRNA.12 This concept was developed as miR-17 family members (with conserved dependent pathway.29 However, to date, the “cellular endogenous RNA” (ceRNA) seed sites and near identical 30end sequen- there are no reports pinning these motifs hypothesis to coincide with additional ces) are all downregulated during infec- to miRNA degradation.