Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency.
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.
Iizasa
Hisashi
H
From the The Wistar Institute, Philadelphia, Pennsylvania 19104; Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Wulff
Bjorn-Erik
BE
From the The Wistar Institute, Philadelphia, Pennsylvania 19104.
Alla
Nageswara R
NR
From the The Wistar Institute, Philadelphia, Pennsylvania 19104.
Maragkakis
Manolis
M
Institute of Molecular Oncology, Biomedical Sciences Research Center Alexander Fleming, 16672 Vari-Athens, Greece; Institute of Computer Science, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany.
Megraw
Molly
M
Department of Genetics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Hatzigeorgiou
Artemis
A
Institute of Molecular Oncology, Biomedical Sciences Research Center Alexander Fleming, 16672 Vari-Athens, Greece.
Iwakiri
Dai
D
Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Takada
Kenzo
K
Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Wiedmer
Andreas
A
From the The Wistar Institute, Philadelphia, Pennsylvania 19104.
Showe
Louise
L
From the The Wistar Institute, Philadelphia, Pennsylvania 19104.
Lieberman
Paul
P
From the The Wistar Institute, Philadelphia, Pennsylvania 19104.
Nishikura
Kazuko
K
From the The Wistar Institute, Philadelphia, Pennsylvania 19104. Electronic address: kazuko@wistar.org.
D045744:Cell Line, Tumor; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000378:metabolism; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017393:RNA Editing / Q000502:physiology*; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D017735:Virus Latency / Q000502:physiology*
C068382:BRLF1 protein, Human herpesvirus 4; C063676:BZLF1 protein, Herpesvirus 4, Human; C402641:EBNA-2 protein, Human herpesvirus 4; D019309:Epstein-Barr Virus Nuclear Antigens; D017874:Immediate-Early Proteins; D035683:MicroRNAs; D012367:RNA, Viral; D015534:Trans-Activators; D014764:Viral Proteins; D043244:Ribonuclease III