Molecular Microbiology and Structural Biochemistry, MMSB-IBCP UMR5086 CNRS, Univ Lyon1, 7 passage du Vercors, 69367, Lyon Cedex 7, France.
Laboratory of Biology and Modelling of the Cell, ENS de Lyon, Univ Claude Bernard Lyon 1, CNRS UMR 5239, INSERM U1210, 46 allée d'Italie, 69364, Lyon, France.
Nat Commun. 2018 Jan 30;9(1):431. doi: 10.1038/s41467-017-02793-6.
Up-Frameshift Suppressor 1 Homolog (UPF1) is a key factor for nonsense-mediated mRNA decay (NMD), a cellular process that can actively degrade mRNAs. Here, we study NMD inhibition during infection by human T-cell lymphotropic virus type I (HTLV-1) and characterise the influence of the retroviral Tax factor on UPF1 activity. Tax interacts with the central helicase core domain of UPF1 and might plug the RNA channel of UPF1, reducing its affinity for nucleic acids. Furthermore, using a single-molecule approach, we show that the sequential interaction of Tax with a RNA-bound UPF1 freezes UPF1: this latter is less sensitive to the presence of ATP and shows translocation defects, highlighting the importance of this feature for NMD. These mechanistic insights reveal how HTLV-1 hijacks the central component of NMD to ensure expression of its own genome.
UPF1 同源物（UPF1）是无义介导的 mRNA 降解（NMD）的关键因素，NMD 是一种可以主动降解 mRNA 的细胞过程。在这里，我们研究了人类 T 细胞白血病病毒 I 型（HTLV-1）感染期间的 NMD 抑制，并描述了逆转录病毒 Tax 因子对 UPF1 活性的影响。Tax 与 UPF1 的中心解旋酶核心结构域相互作用，可能堵塞 UPF1 的 RNA 通道，降低其对核酸的亲和力。此外，我们使用单分子方法表明，Tax 与 RNA 结合的 UPF1 的顺序相互作用使 UPF1 失活：后者对 ATP 的存在不敏感，并且显示出易位缺陷，突出了该特性对 NMD 的重要性。这些机制见解揭示了 HTLV-1 如何劫持 NMD 的中心组件来确保其自身基因组的表达。
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