IGH, CNRS, Université de Montpellier, Montpellier, France.
Next-Generation Sequencing Core Facility, UMS2008 IBSLor CNRS-University of Lorraine-INSERM, BioPole, Vandoeuvre-les-Nancy, France.
Nature. 2019 Jan;565(7740):500-504. doi: 10.1038/s41586-018-0841-4. Epub 2019 Jan 9.
In mammals, 2'-O-methylation of RNA is a molecular signature by which the cellular innate immune system distinguishes endogenous from exogenous messenger RNA. However, the molecular functions of RNA 2'-O-methylation are not well understood. Here we have purified TAR RNA-binding protein (TRBP) and its interacting partners and identified a DICER-independent TRBP complex containing FTSJ3, a putative 2'-O-methyltransferase (2'O-MTase). In vitro and ex vivo experiments show that FTSJ3 is a 2'O-MTase that is recruited to HIV RNA through TRBP. Using RiboMethSeq analysis, we identified predominantly FTSJ3-dependent 2'-O-methylations at specific residues on the viral genome. HIV-1 viruses produced in FTSJ3 knockdown cells show reduced 2'-O-methylation and trigger expression of type 1 interferons (IFNs) in human dendritic cells through the RNA sensor MDA5. This induction of IFN-α and IFN-β leads to a reduction in HIV expression. We have identified an unexpected mechanism used by HIV-1 to evade innate immune recognition: the recruitment of the TRBP-FTSJ3 complex to viral RNA and its 2'-O-methylation.
在哺乳动物中，RNA 的 2'-O-甲基化是细胞固有免疫系统区分内源性和外源性信使 RNA 的分子特征。然而，RNA 2'-O-甲基化的分子功能尚不清楚。在这里，我们纯化了 TAR RNA 结合蛋白 (TRBP) 及其相互作用的伙伴，并鉴定了一种不含 DICER 的 TRBP 复合物，其中包含 FTSJ3，一种假定的 2'-O-甲基转移酶 (2'O-MTase)。体外和离体实验表明，FTSJ3 是一种 2'O-MTase，可通过 TRBP 募集到 HIV RNA。使用 RiboMethSeq 分析，我们鉴定了在病毒基因组的特定残基上主要依赖于 FTSJ3 的 2'-O-甲基化。在 FTSJ3 敲低细胞中产生的 HIV-1 病毒显示出 2'-O-甲基化减少，并通过 RNA 传感器 MDA5 在人树突状细胞中触发 I 型干扰素 (IFN) 的表达。IFN-α 和 IFN-β 的这种诱导导致 HIV 表达减少。我们已经确定了 HIV-1 逃避先天免疫识别的一种意外机制：TRBP-FTSJ3 复合物被招募到病毒 RNA 及其 2'-O-甲基化。
