Posttranscriptional m(6)A Editing of HIV-1 mRNAs Enhances Viral Gene Expression.
Posttranscriptional m(6)A Editing of HIV-1 mRNAs Enhances Viral Gene Expression.
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DOI：
10.1016/j.chom.2016.04.002
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发表时间：
2016-05-11
影响因子：
30.3
通讯作者：
Cullen BR
中科院分区：
文献类型：
--
作者：
Kennedy EM;Bogerd HP;Kornepati AV;Kang D;Ghoshal D;Marshall JB;Poling BC;Tsai K;Gokhale NS;Horner SM;Cullen BR
腺苷N6（m6 A）上的甲基共价加成是一种进化上保守且常见的RNA修饰，被认为调节RNA代谢的几个方面。虽然在近40年前就报道了不同病毒RNA上存在多个m6 A编辑位点，但m6 A编辑如何影响病毒复制仍不清楚。在这里，我们使用光交联辅助m6 A测序技术精确地绘制了HIV-1基因组上的几个m6 A编辑位点，并报告它们聚集在HIV-1 3'非翻译区（3' UTR）。病毒3 'UTR m6 A位点或类似的细胞m6 A位点通过募集细胞YTHDF m6 A“阅读器”蛋白强烈增强mRNA顺式表达。减少YTHDF表达抑制，而YTHDF过表达增强，HIV-1蛋白和RNA表达，以及病毒在CD 4 + T细胞中的复制。这些数据确定了m6 A编辑，以及由此产生的YTHDF蛋白的募集，作为HIV-1 mRNA表达的主要正调控因子。
Covalent addition of a methyl group to the adenosine N6 (m6A) is an evolutionarily conserved and common RNA modification that is thought to modulate several aspects of RNA metabolism. While the presence of multiple m6A editing sites on diverse viral RNAs was reported starting almost 40 years ago, how m6A editing affects virus replication has remained unclear. Here, we used photo-crosslinking-assisted m6A sequencing techniques to precisely map several m6A editing sites on the HIV-1 genome and report that they cluster in the HIV-1 3’ untranslated region (3'UTR). Viral 3'UTR m6A sites or analogous cellular m6A sites strongly enhanced mRNA expression in cis by recruiting the cellular YTHDF m6A “reader” proteins. Reducing YTHDF expression inhibited, while YTHDF overexpression enhanced, HIV-1 protein and RNA expression, and virus replication in CD4+ T cells. These data identify m6A editing, and the resultant recruitment of YTHDF proteins, as major positive regulators of HIV-1 mRNA expression.