IRES-mediated translation during cellular stress

细胞有两种不同的方式产生蛋白质，即帽依赖翻译和内部核糖体进入位点介导的翻译。大多数细胞蛋白是通过帽依赖翻译产生的，而大约5%的细胞mRNA和某些病毒mRNA是通过ires介导的翻译产生的。我们仍然没有一个明确的答案，为什么哺乳动物细胞有两个不同的翻译系统。众所周知，当帽帽依赖性翻译在细胞应激和病毒感染下严重受损时，ires介导的翻译通常是活跃的或维持的。因此，假设ires介导的翻译在应激条件下维持细胞稳态，作为帽依赖翻译的备份，这是一种故障安全策略。对于病毒而言，IRES元件驱动的翻译机制可能是其复制的一大优势，因为在细胞死亡期间可以实现病毒蛋白的有效合成。我们实验室的长期研究目标是研究细胞如何在不同的细胞环境中调控这两种翻译机制。在当前NSERC资助期间（2006-2011），我们发现氨基酸饥饿提高了口蹄疫病毒（FMDV） IRES元件启动的翻译效率。在拟议的研究中，我们将研究在氨基酸饥饿期间FMDV如何增加蛋白质合成的细胞机制。该研究将在翻译控制、病毒学和细胞生理学等领域产生重大影响。为了了解蛋白质合成是如何被调控的，我们必须继续研究ires介导的翻译的机制，并培养下一代的研究人员。

Cells have two distinct ways to generate proteins which are cap-dependent translation and internal ribosomal entry site (IRES) mediated translation. The majority of cellular proteins are generated via cap-dependent translation while approximately 5% of cellular mRNA and certain viral mRNA are translated by IRES-mediated translation. We still do not have a clear answer as to why mammalian cells have two distinct translation systems. It is known that IRES-mediated translation is often active or maintained when cap-dependent translation is severely impaired under cellular stress and virus infection. Therefore, it is assumed that it is a fail-safe strategy in which IRES-mediated translation maintains cellular homeostasis as a backup of cap-dependent translation under stress conditions. For viruses, the translational machinery driven by IRES elements may be a great advantage for their replication since efficient synthesis of viral proteins can be achieved during cell death. The long-term research goal of our laboratory is to study how cells regulate the two translational machineries in different cellular environment. During the current NSERC funding period (2006-2011), we found that amino acid starvation increase translation efficiency initiated by foot-and-mouth disease virus (FMDV) IRES element. In the proposed study, we will investigate cellular mechanisms of how protein synthesis by FMDV is increased during amino acid starvation. The proposed study will have a significant impact in the field of translational control, virology and cell physiology. In order to understand how protein synthesis is regulated, it is essential that we continue to investigate the mechanisms that underlie IRES-mediated translation and to train the next generation of researchers.