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Editing of Epstein-Barr Virus-encoded BART6 MicroRNAs Controls Their Dicer Targeting and Consequently Affects Viral Latency*

Open AccessPublished:August 17, 2010DOI:https://doi.org/10.1074/jbc.M110.138362
      Certain primary transcripts of miRNA (pri-microRNAs) undergo RNA editing that converts adenosine to inosine. The Epstein-Barr virus (EBV) genome encodes multiple microRNA genes of its own. Here we report that primary transcripts of ebv-miR-BART6 (pri-miR-BART6) are edited in latently EBV-infected cells. Editing of wild-type pri-miR-BART6 RNAs dramatically reduced loading of miR-BART6-5p RNAs onto the microRNA-induced silencing complex. Editing of a mutation-containing pri-miR-BART6 found in Daudi Burkitt lymphoma and nasopharyngeal carcinoma C666-1 cell lines suppressed processing of miR-BART6 RNAs. Most importantly, miR-BART6-5p RNAs silence Dicer through multiple target sites located in the 3′-UTR of Dicer mRNA. The significance of miR-BART6 was further investigated in cells in various stages of latency. We found that miR-BART6-5p RNAs suppress the EBNA2 viral oncogene required for transition from immunologically less responsive type I and type II latency to the more immunoreactive type III latency as well as Zta and Rta viral proteins essential for lytic replication, revealing the regulatory function of miR-BART6 in EBV infection and latency. Mutation and A-to-I editing appear to be adaptive mechanisms that antagonize miR-BART6 activities.

      Introduction

      MicroRNAs (miRNAs)
      The abbreviations used are: miRNA
      microRNA
      ADAR
      adenosine deaminases acting on RNA
      miRISC
      miRNA-induced silencing complex
      EBV
      Epstein-Barr virus
      qRT
      quantitative real-time.
      play important roles in many processes including development, differentiation, proliferation, and apoptosis (,
      • Stefani G.
      • Slack F.J.
      ). Certain miRNAs act as tumor suppressors or oncogenes and are associated with many cancers (
      • Esquela-Kerscher A.
      • Slack F.J.
      ). Primary transcripts of miRNA genes (pri-miRNAs) are processed sequentially by Drosha and Dicer (
      • Kim V.N.
      • Han J.
      • Siomi M.C.
      ,
      • Winter J.
      • Jung S.
      • Keller S.
      • Gregory R.I.
      • Diederichs S.
      ). Nuclear Drosha (
      • Lee Y.
      • Ahn C.
      • Han J.
      • Choi H.
      • Kim J.
      • Yim J.
      • Lee J.
      • Provost P.
      • Rådmark O.
      • Kim S.
      • Kim V.N.
      ) together with its partner DGCR8 (
      • Denli A.M.
      • Tops B.B.
      • Plasterk R.H.
      • Ketting R.F.
      • Hannon G.J.
      ,
      • Gregory R.I.
      • Yan K.P.
      • Amuthan G.
      • Chendrimada T.
      • Doratotaj B.
      • Cooch N.
      • Shiekhattar R.
      ) cleaves pri-miRNAs, releasing 60–70-nucleotide pre-miRNAs. Recognition of correctly processed pre-miRNAs and their nuclear export is carried out by exportin-5 and RanGTP (
      • Lund E.
      • Güttinger S.
      • Calado A.
      • Dahlberg J.E.
      • Kutay U.
      ). Cytoplasmic Dicer together with the double-stranded RNA (dsRNA)-binding protein TRBP then cleaves pre-miRNAs into 20–22-nucleotide siRNA-like duplexes (
      • Chendrimada T.P.
      • Gregory R.I.
      • Kumaraswamy E.
      • Norman J.
      • Cooch N.
      • Nishikura K.
      • Shiekhattar R.
      ,
      • Förstemann K.
      • Tomari Y.
      • Du T.
      • Vagin V.V.
      • Denli A.M.
      • Bratu D.P.
      • Klattenhoff C.
      • Theurkauf W.E.
      • Zamore P.D.
      ). In most cases one strand of the duplex (called the effective strand) serves as the mature miRNA, whereas the other strand (called passenger strand) is eliminated. After integration into the miRNA-induced silencing complex (miRISC), miRNAs block translation via partially complementary binding sites located in the 3′-UTRs of targeted mRNAs or guide the degradation of target mRNAs after binding, mainly via the 5′ half of the miRNA sequence, called the “seed sequence” (,
      • Kim V.N.
      • Han J.
      • Siomi M.C.
      ,
      • Winter J.
      • Jung S.
      • Keller S.
      • Gregory R.I.
      • Diederichs S.
      ).
      Epstein-Barr Virus (EBV) causes mononucleosis during acute and lytic infection and also establishes a persistent and latent infection in the human host. Latently infected EBV has been demonstrated to be associated with a variety of human cancers such as Burkitt lymphoma, Hodgkin disease, and nasopharyngeal carcinoma (
      • Hislop A.D.
      • Taylor G.S.
      • Sauce D.
      • Rickinson A.B.
      ,
      • Pagano J.S.
      • Blaser M.
      • Buendia M.A.
      • Damania B.
      • Khalili K.
      • Raab-Traub N.
      • Roizman B.
      ). Lytic infection and transition to distinctive states of latency (type I-III) are regulated by select viral genes and their interaction with the host immune system (
      • Hislop A.D.
      • Taylor G.S.
      • Sauce D.
      • Rickinson A.B.
      ,
      • Pagano J.S.
      • Blaser M.
      • Buendia M.A.
      • Damania B.
      • Khalili K.
      • Raab-Traub N.
      • Roizman B.
      ). Virus genomes encode miRNAs of their own, and the first viral miRNA was identified in human B cells infected with EBV (
      • Pfeffer S.
      • Zavolan M.
      • Grässer F.A.
      • Chien M.
      • Russo J.J.
      • Ju J.
      • John B.
      • Enright A.J.
      • Marks D.
      • Sander C.
      • Tuschl T.
      ). A total of 23 EBV miRNA genes are known and located in the BHRF1 and BART (Bam H1 A rightward transcript) regions of the genome (
      • Cai X.
      • Schäfer A.
      • Lu S.
      • Bilello J.P.
      • Desrosiers R.C.
      • Edwards R.
      • Raab-Traub N.
      • Cullen B.R.
      ,
      • Edwards R.H.
      • Marquitz A.R.
      • Raab-Traub N.
      ,
      • Grundhoff A.
      • Sullivan C.S.
      • Ganem D.
      ). These EBV miRNAs have been implicated in regulating the transition from lytic replication to latent infection and in attenuating antiviral immune responses (
      • Cullen B.R.
      ). However, only a limited number of their targets have been identified so far. The viral miRNAs seem to target both viral and host cell genes (
      • Cullen B.R.
      ). For instance, miR-BART2 targets the EBV DNA polymerase, BALF5, perhaps promoting entry of the virus to latency by slowing down viral replication at the transition point from lytic to latent infection (
      • Barth S.
      • Pfuhl T.
      • Mamiani A.
      • Ehses C.
      • Roemer K.
      • Kremmer E.
      • Jäker C.
      • Höck J.
      • Meister G.
      • Grässer F.A.
      ). Down-regulation of the EBV protein LMP1 by three EBV miRNAs, miR-BART1–5p, miR-BART16, and miR-BART17–5p, has been reported (
      • Lo A.K.
      • To K.F.
      • Lo K.W.
      • Lung R.W.
      • Hui J.W.
      • Liao G.
      • Hayward S.D.
      ). LMP1 produced during the EBV type II and III latency controls the NF-κβ signaling pathway and growth and apoptosis of host cells. Targeting of host cell genes PUMA (p53-up-regulated modulator of apoptosis) by miR-BART5 (
      • Choy E.Y.
      • Siu K.L.
      • Kok K.H.
      • Lung R.W.
      • Tsang C.M.
      • To K.F.
      • Kwong D.L.
      • Tsao S.W.
      • Jin D.Y.
      ) and CXC-chemokine ligand 11 (CXCL11) by miR-BHRF1–3 (
      • Xia T.
      • O'Hara A.
      • Araujo I.
      • Barreto J.
      • Carvalho E.
      • Sapucaia J.B.
      • Ramos J.C.
      • Luz E.
      • Pedroso C.
      • Manrique M.
      • Toomey N.L.
      • Brites C.
      • Dittmer D.P.
      • Harrington Jr., W.J.
      ) have been reported. Down-regulation of PUMA may suppress apoptosis of virus-infected host cells (
      • Choy E.Y.
      • Siu K.L.
      • Kok K.H.
      • Lung R.W.
      • Tsang C.M.
      • To K.F.
      • Kwong D.L.
      • Tsao S.W.
      • Jin D.Y.
      ), whereas suppression of CXCL11 may shield EBV-infected B cells from cytotoxic T cells (
      • Xia T.
      • O'Hara A.
      • Araujo I.
      • Barreto J.
      • Carvalho E.
      • Sapucaia J.B.
      • Ramos J.C.
      • Luz E.
      • Pedroso C.
      • Manrique M.
      • Toomey N.L.
      • Brites C.
      • Dittmer D.P.
      • Harrington Jr., W.J.
      ).
      One type of RNA editing involves the conversion of adenosine residues into inosine (A-to-I editing) in dsRNA through the action of adenosine deaminase acting on RNA (ADAR). Three ADAR gene family members (ADAR1–3) have been identified in humans and rodents (
      • Bass B.L.
      ,
      • Nishikura K.
      ). The translation machinery reads an inosine as if it were guanosine, which could lead to codon changes (
      • Basilio C.
      • Wahba A.J.
      • Lengyel P.
      • Speyer J.F.
      • Ochoa S.
      ). Thus, when A-to-I RNA editing occurs within a coding sequence, synthesis of proteins not directly encoded by the genome can result, as demonstrated with transcripts of glutamate receptor ion channels and 5-HT2C serotonin receptors (
      • Jepson J.E.
      • Reenan R.A.
      ). However, the most common targets for A-to-I editing are non-coding RNAs that contain inverted repeats of repetitive elements such as Alu elements and LINEs located within introns and 3′-UTRs (
      • Athanasiadis A.
      • Rich A.
      • Maas S.
      ,
      • Blow M.
      • Futreal P.A.
      • Wooster R.
      • Stratton M.R.
      ,
      • Kim D.D.
      • Kim T.T.
      • Walsh T.
      • Kobayashi Y.
      • Matise T.C.
      • Buyske S.
      • Gabriel A.
      ,
      • Levanon E.Y.
      • Eisenberg E.
      • Yelin R.
      • Nemzer S.
      • Hallegger M.
      • Shemesh R.
      • Fligelman Z.Y.
      • Shoshan A.
      • Pollock S.R.
      • Sztybel D.
      • Olshansky M.
      • Rechavi G.
      • Jantsch M.F.
      ). The biological significance of non-coding, repetitive RNA editing is largely unknown. Furthermore, editing of certain pri-miRNAs has been reported (
      • Blow M.J.
      • Grocock R.J.
      • van Dongen S.
      • Enright A.J.
      • Dicks E.
      • Futreal P.A.
      • Wooster R.
      • Stratton M.R.
      ,
      • Luciano D.J.
      • Mirsky H.
      • Vendetti N.J.
      • Maas S.
      ). A recent survey has revealed that ∼20% of human pri-miRNAs are subject to A-to-I RNA editing catalyzed by ADAR1 and ADAR2 (
      • Kawahara Y.
      • Megraw M.
      • Kreider E.
      • Iizasa H.
      • Valente L.
      • Hatzigeorgiou A.G.
      • Nishikura K.
      ). Editing of pri-miRNAs modulates expression and function of miRNAs (
      • Kawahara Y.
      • Megraw M.
      • Kreider E.
      • Iizasa H.
      • Valente L.
      • Hatzigeorgiou A.G.
      • Nishikura K.
      ). For instance, A-to-I editing of several adenosine residues located near the Drosha cleavage sites of pri-miRNA-142 results in inhibition of the processing by Drosha and consequent down-regulation of mature miR-142 RNAs (
      • Yang W.
      • Chendrimada T.P.
      • Wang Q.
      • Higuchi M.
      • Seeburg P.H.
      • Shiekhattar R.
      • Nishikura K.
      ), whereas editing of two sites identified near the end loop of the pri-miR-151 hairpin structure inhibits the Dicer cleavage step (
      • Kawahara Y.
      • Zinshteyn B.
      • Chendrimada T.P.
      • Shiekhattar R.
      • Nishikura K.
      ). By contrast, editing of primary transcripts of the miR-376 cluster at two sites located within the seed sequence does not affect their processing but results in expression of mature-edited miR-376 RNAs with altered seed sequences and consequent silencing of a set of genes different from those targeted by unedited miR-376 RNAs (
      • Kawahara Y.
      • Zinshteyn B.
      • Sethupathy P.
      • Iizasa H.
      • Hatzigeorgiou A.G.
      • Nishikura K.
      ).
      In this study we set out to examine editing of EBV miRNAs in EBV-transformed lymphoblastoid GM607 cells, Burkitt lymphoma Daudi cells, and nasopharyngeal carcinoma C666-1 cells. Human lymphoblastoid cells such as GM607 cells in type III latency express a set of genes essential for this specific state of latency, such as EBNA2 and LMP1. By contrast, Daudi Burkitt lymphoma cells in the restricted sub-type of type III latency do not express EBNA2 due to the genomic deletion (
      • Kelly G.L.
      • Milner A.E.
      • Tierney R.J.
      • Croom-Carter D.S.
      • Altmann M.
      • Hammerschmidt W.
      • Bell A.I.
      • Rickinson A.B.
      ,
      • Cheung S.T.
      • Huang D.P.
      • Hui A.B.
      • Lo K.W.
      • Ko C.W.
      • Tsang Y.S.
      • Wong N.
      • Whitney B.M.
      • Lee J.C.
      ). Viral infection in C666-1 nasopharyngeal carcinoma cells is associated with more restricted forms of type II latency, which expresses only a limited number of viral genes, representing a less immune-responsive state (
      • Cheung S.T.
      • Huang D.P.
      • Hui A.B.
      • Lo K.W.
      • Ko C.W.
      • Tsang Y.S.
      • Wong N.
      • Whitney B.M.
      • Lee J.C.
      ). We have found that primary transcripts of four EBV miRNAs, including miR-BART6, are subject to A-to-I editing. Moreover, we demonstrate that editing of pri-miR BART6 RNAs as well as mutations of miR-BART6 RNAs found in latently EBV-infected cells inhibits expression or their loading onto the functionally active miRISC. Most significantly, we found that miR-BART6 targets Dicer and affects the latent state of EBV viral infection. Regulation of the miR-BART6 expression and function through A-to-I editing and mutation may be critical for the establishment or maintenance of latent EBV infection.

      Acknowledgments

      We thank L. Valente and W. Deng for providing purified Drosha-DGCR8, Dicer-TRBP, and Ago2-Dicer-TRBP complexes and J. M. Murray and B. Zinshteyn for comments.

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