Bridge Katherine S, Shah Kunal M, Li Yigen, Foxler Daniel E, Wong Sybil C K, Miller Duncan C, Davidson Kathryn M, Foster John G, Rose Ruth, Hodgkinson Michael R, Ribeiro Paulo S, Aboobaker A Aziz, Yashiro Kenta, Wang Xiaozhong, Graves Paul R, Plevin Michael J, Lagos Dimitris, Sharp Tyson V
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
School of Biological and Chemical Sciences, Queen Mary University of London, Fogg Building, Mile End Road, London E1 4NS, UK.
Cell Rep. 2017 Jul 5;20(1):173-187. doi: 10.1016/j.celrep.2017.06.027.
As core components of the microRNA-induced silencing complex (miRISC), Argonaute (AGO) proteins interact with TNRC6 proteins, recruiting other effectors of translational repression/mRNA destabilization. Here, we show that LIMD1 coordinates the assembly of an AGO-TNRC6 containing miRISC complex by binding both proteins simultaneously at distinct interfaces. Phosphorylation of AGO2 at Ser 387 by Akt3 induces LIMD1 binding, which in turn enables AGO2 to interact with TNRC6A and downstream effector DDX6. Conservation of this serine in AGO1 and 4 indicates this mechanism may be a fundamental requirement for AGO function and miRISC assembly. Upon CRISPR-Cas9-mediated knockout of LIMD1, AGO2 miRNA-silencing function is lost and miRNA silencing becomes dependent on a complex formed by AGO3 and the LIMD1 family member WTIP. The switch to AGO3 utilization occurs due to the presence of a glutamic acid residue (E390) on the interaction interface, which allows AGO3 to bind to LIMD1, AJUBA, and WTIP irrespective of Akt signaling.
作为微小RNA诱导沉默复合体（miRISC）的核心组分，AGO蛋白与TNRC6蛋白相互作用，招募翻译抑制/信使核糖核酸（mRNA）去稳定化的其他效应器。在此，我们表明，LIMD1通过在不同界面同时结合这两种蛋白来协调含AGO-TNRC6的miRISC复合体的组装。Akt3使AGO2的丝氨酸387位点磷酸化，诱导LIMD1结合，这进而使AGO2与TNRC6A及下游效应器DDX6相互作用。AGO1和AGO4中该丝氨酸的保守性表明，此机制可能是AGO功能和miRISC组装的基本要求。在CRISPR-Cas9介导敲除LIMD1后，AGO2的微小RNA沉默功能丧失，微小RNA沉默变得依赖于AGO3与LIMD1家族成员WTIP形成的复合体。向利用AGO3的转变是由于相互作用界面上存在一个谷氨酸残基（E390），这使得AGO3无论Akt信号传导如何都能与LIMD1、AJUBA和WTIP结合。
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