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

• Published in: The Journal of biological chemistry 2010-10, Vol.285 (43), p.33358-33370
• Main Authors: Iizasa, Hisashi, Wulff, Bjorn-Erik, Alla, Nageswara R., Maragkakis, Manolis, Megraw, Molly, Hatzigeorgiou, Artemis, Iwakiri, Dai, Takada, Kenzo, Wiedmer, Andreas, Showe, Louise, Lieberman, Paul, Nishikura, Kazuko
• Format: Article
• Language: English
• Subjects: ADAR; Cell Line, Tumor; Dicer; Double-stranded RNA; Epstein-Barr Virus; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - metabolism; Epstein-Barr Virus Nuclear Antigens - genetics; Epstein-Barr Virus Nuclear Antigens - metabolism; Gene Regulation; Gene Silencing - physiology; Herpesvirus 4, Human - physiology; Humans; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Ribonuclease III - genetics; Ribonuclease III - metabolism; RNA; RNA Editing; RNA Editing - physiology; RNA, Viral - genetics; RNA, Viral - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; Viral Proteins - genetics; Viral Proteins - metabolism; Virus Latency; Virus Latency - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 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.