Jaafar Zane A, Oguro Akihiro, Nakamura Yoshikazu, Kieft Jeffrey S
Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, United States.
Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Elife. 2016 Dec 23;5:e21198. doi: 10.7554/eLife.21198.
Internal ribosome entry sites (IRESs) are important RNA-based translation initiation signals, critical for infection by many pathogenic viruses. The hepatitis C virus (HCV) IRES is the prototype for the type 3 IRESs and is also invaluable for exploring principles of eukaryotic translation initiation, in general. Current mechanistic models for the type 3 IRESs are useful but they also present paradoxes, including how they can function both with and without eukaryotic initiation factor (eIF) 2. We discovered that eIF1A is necessary for efficient activity where it stabilizes tRNA binding and inspects the codon-anticodon interaction, especially important in the IRES' eIF2-independent mode. These data support a model in which the IRES binds preassembled translation preinitiation complexes and remodels them to generate eukaryotic initiation complexes with bacterial-like features. This model explains previous data, reconciles eIF2-dependent and -independent pathways, and illustrates how RNA structure-based control can respond to changing cellular conditions.
内部核糖体进入位点（IRES）是重要的基于RNA的翻译起始信号，对许多致病病毒的感染至关重要。丙型肝炎病毒（HCV）IRES是3型IRES的原型，总体而言，对于探索真核生物翻译起始的原理也非常重要。目前关于3型IRES的机制模型很有用，但也存在一些矛盾之处，包括它们如何在有和没有真核起始因子（eIF）2的情况下发挥作用。我们发现，eIF1A对于高效活性是必需的，它能稳定tRNA结合并检查密码子-反密码子相互作用，这在IRES的eIF2非依赖模式中尤为重要。这些数据支持了一个模型，即IRES结合预先组装的翻译起始前复合物并对其进行重塑，以生成具有类似细菌特征的真核起始复合物。该模型解释了先前的数据，协调了eIF2依赖和非依赖途径，并说明了基于RNA结构的控制如何响应不断变化的细胞条件。
