Editing of Epstein-Barr Virus-encoded BART6 MicroRNAs Controls Their Dicer Targeting and Consequently Affects Viral Latency
Editing of Epstein-Barr Virus-encoded BART6 MicroRNAs Controls Their Dicer Targeting and Consequently Affects Viral Latency
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DOI：
10.1074/jbc.m110.138362
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发表时间：
2010-10-22
影响因子：
4.8
通讯作者：
Nishikura, Kazuko
中科院分区：
文献类型：
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作者：
Iizasa, Hisashi;Wulff, Bjorn-Erik;Nishikura, Kazuko
miRNA的某些初级转录物（pri-microRNA）经历将腺苷转化为肌苷的RNA编辑。EB病毒（EBV）基因组编码其自身的多个microRNA基因。在这里，我们报告了ebv-miR-BART 6（pri-miR-BART 6）的初级转录本在潜伏性EBV感染的细胞中被编辑。编辑野生型pri-miR-BART 6 RNA显著减少了miR-BART 6 - 5 p RNA加载到microRNA诱导的沉默复合物上。编辑Daudi Burkitt淋巴瘤和鼻咽癌C666-1细胞系中发现的含有突变的pri-miR-BART 6抑制了miR-BART 6 RNA的加工最重要的是，miR-BART 6 - 5 p RNA通过位于Dicer mRNA的3 '-UTR中的多个靶位点使Dicer沉默。在不同潜伏期阶段的细胞中进一步研究miR-BART 6的意义。我们发现miR-BART 6 - 5 p RNA抑制了从免疫反应性较低的I型和II型潜伏期转变为免疫反应性较高的III型潜伏期所需的EBNA 2病毒癌基因以及裂解性复制所必需的Zta和Rta病毒蛋白，揭示了miR-BART 6在EBV感染和潜伏期中的调节功能。突变和A-to-I编辑似乎是拮抗miR-BART 6活性的适应性机制。
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.