Tahiri-Alaoui Abdessamad, Zhao Yuguang, Sadigh Yashar, Popplestone James, Kgosana Lydia, Smith Lorraine P, Nair Venugopal
The Pirbright Institute, Ash Road, Pirbright, Woking, Surrey, United Kingdom.
The Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, United Kingdom.
PLoS One. 2014 Dec 11;9(12):e114466. doi: 10.1371/journal.pone.0114466. eCollection 2014.
Poly(A) binding protein 1 (PABP1) plays a central role in mRNA translation and stability and is a target by many viruses in diverse manners. We report a novel viral translational control strategy involving the recruitment of PABP1 to the 5' leader internal ribosome entry site (5L IRES) of an immediate-early (IE) bicistronic mRNA that encodes the neurovirulence protein (pp14) from the avian herpesvirus Marek's disease virus serotype 1 (MDV1). We provide evidence for the interaction between an internal poly(A) sequence within the 5L IRES and PABP1 which may occur concomitantly with the recruitment of PABP1 to the poly(A) tail. RNA interference and reverse genetic mutagenesis results show that a subset of virally encoded-microRNAs (miRNAs) targets the inhibitor of PABP1, known as paip2, and therefore plays an indirect role in PABP1 recruitment strategy by increasing the available pool of active PABP1. We propose a model that may offer a mechanistic explanation for the cap-independent enhancement of the activity of the 5L IRES by recruitment of a bona fide initiation protein to the 5' end of the message and that is, from the affinity binding data, still compatible with the formation of 'closed loop' structure of mRNA.
聚腺苷酸结合蛋白1（PABP1）在mRNA翻译和稳定性中起核心作用，并且是许多病毒以不同方式作用的靶点。我们报道了一种新的病毒翻译控制策略，该策略涉及将PABP1募集到一个立即早期（IE）双顺反子mRNA的5'前导区内核糖体进入位点（5L IRES），该mRNA编码来自禽疱疹病毒1型马立克氏病病毒（MDV1）的神经毒力蛋白（pp14）。我们提供了5L IRES内的内部聚腺苷酸序列与PABP1之间相互作用的证据，这种相互作用可能与PABP1募集到聚腺苷酸尾同时发生。RNA干扰和反向遗传诱变结果表明，一部分病毒编码的微小RNA（miRNA）靶向PABP1的抑制剂paip2，因此通过增加活性PABP1的可用量在PABP1募集策略中发挥间接作用。我们提出了一个模型，该模型可能为通过将一个真正的起始蛋白募集到信使RNA的5'末端来实现5L IRES活性的不依赖帽的增强提供一个机制解释，并且从亲和力结合数据来看，该模型仍然与mRNA“闭环”结构的形成相容。
