Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Mol Cell. 2023 Jul 20;83(14):2478-2492.e8. doi: 10.1016/j.molcel.2023.06.001. Epub 2023 Jun 26.
The RNA-binding protein TRIM71/LIN-41 is a phylogenetically conserved developmental regulator that functions in mammalian stem cell reprogramming, brain development, and cancer. TRIM71 recognizes target mRNAs through hairpin motifs and silences them through molecular mechanisms that await identification. Here, we uncover that TRIM71 represses its targets through RNA-supported interaction with TNRC6/GW182, a core component of the miRNA-induced silencing complex (miRISC). We demonstrate that AGO2, TRIM71, and UPF1 each recruit TNRC6 to specific sets of transcripts to silence them. As cellular TNRC6 levels are limiting, competition occurs among the silencing pathways, such that the loss of AGO proteins or of AGO binding to TNRC6 enhances the activities of the other pathways. We conclude that a miRNA-like silencing activity is shared among different mRNA silencing pathways and that the use of TNRC6 as a central hub provides a means to integrate their activities.
RNA 结合蛋白 TRIM71/LIN-41 是一种进化上保守的发育调控因子，它在哺乳动物干细胞重编程、大脑发育和癌症中发挥作用。TRIM71 通过发夹结构识别靶 mRNA，并通过有待鉴定的分子机制使其沉默。在这里，我们发现 TRIM71 通过与 TNRC6/GW182 的 RNA 支持的相互作用来抑制其靶标，TNRC6/GW182 是 microRNA 诱导的沉默复合物 (miRISC) 的核心组成部分。我们证明 AGO2、TRIM71 和 UPF1 各自将 TNRC6 招募到特定的转录本集以使其沉默。由于细胞内 TNRC6 水平是有限的，因此在沉默途径之间会发生竞争，例如 AGO 蛋白的缺失或 AGO 与 TNRC6 的结合会增强其他途径的活性。我们得出结论，不同的 mRNA 沉默途径共享类似 miRNA 的沉默活性，并且将 TNRC6 用作中央枢纽提供了一种整合它们活性的方法。
