Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
Proc Natl Acad Sci U S A. 2017 May 23;114(21):5425-5430. doi: 10.1073/pnas.1701488114. Epub 2017 May 9.
MicroRNAs (miRNAs) play critical roles in a broad variety of biological processes by inhibiting translation initiation and by destabilizing target mRNAs. The CCR4-NOT complex effects miRNA-mediated silencing, at least in part through interactions with 4E-T (eIF4E transporter) protein, but the precise mechanism is unknown. Here we show that the cap-binding eIF4E-homologous protein 4EHP is an integral component of the miRNA-mediated silencing machinery. We demonstrate that the cap-binding activity of 4EHP contributes to the translational silencing by miRNAs through the CCR4-NOT complex. Our results show that 4EHP competes with eIF4E for binding to 4E-T, and this interaction increases the affinity of 4EHP for the cap. We propose a model wherein the 4E-T/4EHP interaction engenders a closed-loop mRNA conformation that blocks translational initiation of miRNA targets.
微小 RNA（miRNA）通过抑制翻译起始和破坏靶 mRNA 来在广泛的生物过程中发挥关键作用。CCR4-NOT 复合物对 miRNA 介导的沉默有影响，至少部分是通过与 4E-T（eIF4E 转运蛋白）蛋白相互作用，但确切的机制尚不清楚。在这里，我们表明帽结合 eIF4E 同源蛋白 4EHP 是 miRNA 介导的沉默机制的一个组成部分。我们证明，4EHP 的帽结合活性通过 CCR4-NOT 复合物有助于 miRNA 介导的翻译沉默。我们的结果表明，4EHP 与 eIF4E 竞争与 4E-T 的结合，并且这种相互作用增加了 4EHP 对帽的亲和力。我们提出了一个模型，其中 4E-T/4EHP 相互作用产生了封闭的 mRNA 构象，阻止了 miRNA 靶标的翻译起始。
