The battle for the 5' end: dissecting a novel virus-specific translation mechanism driven by eIF3

我们的目的是了解一种具有临床和经济重要性的病毒产生蛋白质的新机制，并研究它如何有助于逃避宿主的检测。人体内的细胞以多种方式对外界刺激作出反应，其中最常见的是通过基因表达的调节。为了应对外部压力，如感染，细胞可以暂停蛋白质合成或翻译，从而停止对遗传信息的解码。这种防御机制允许细胞通过限制蛋白质合成所需的能量和营养的使用来生存，直到压力被化解。它还可以阻止病毒的传播，因为病毒依赖宿主细胞资源来产生病毒蛋白和复制。正因为如此，病毒已经开发出了使用替代机制生产蛋白质的策略。使用不同的病毒作为模型，我们以前在识别病毒通过调节翻译来操纵宿主细胞的新机制方面取得了重大进展。蚊子传播的病毒是人类和动物健康的主要负担。其中，登革热病毒是一种突出的人类健康威胁，每年在全球范围内造成数百万人感染，没有广泛有效或特定的治疗方法。我们之前已经证明，登革热病毒感染会导致宿主蛋白合成受阻，但病毒蛋白如何翻译以支持病毒传播仍然是一个谜。这一点很重要，因为了解病毒是如何劫持宿主资源的可以揭示病毒盔甲中的一个新的阿喀琉斯之踵。基于我们的结果，我们提出了一种新的机制来翻译登革热病毒蛋白，该机制使用了一种已知的细胞翻译因子eIF3，以一种非传统的方式介导翻译。我们还提出，这种机制可以帮助登革热病毒逃避宿主的检测。因此，我们的目标是1-表征eIF3如何与病毒RNA相互作用；2-阐明这如何有助于一种新的翻译机制；3-建立这种机制如何与宿主对病毒RNA的非自我检测竞争。通过这项工作，我们希望提高我们对病毒如何控制宿主资源的知识，以确保病毒蛋白的生成。这一机制是新颖的，我们认为它代表了病毒进化出的一条新的反防线。因此，它可以帮助确定抑制病毒复制的新方法，并开发针对一组重要病毒的新型抗病毒疗法。了解基因调控的基本机制对病毒学家来说很重要，对更广泛的学术界也是如此。它还可能帮助我们更好地理解几种病理学的基础，如癌症或神经退行性疾病，这些疾病与替代翻译机制有关。

Our aim is to understand a new mechanism of protein production by viruses of clinical and economical importance and examine how it contributes to escaping detection from the host. Cells within the body respond to external stimuli in many ways, the most common of which is via the regulation of gene expression. In response to external stresses such as infection, cells can pause protein synthesis, or translation, and thus the decoding of genetic information. This defense mechanism allows cells to survive by limiting the use of energy and nutrients that protein synthesis requires until the stress is resolved. It also blocks the spread of viruses as viruses are dependent on host cell resources to produce viral proteins and replicate. Because of this, viruses have developed strategies to produce their proteins using alternative mechanisms. Using different viruses as models, we have previously made significant advances in identifying new mechanisms that viruses use to manipulate the host cell by regulating translation. Viruses transmitted by mosquitoes represent a major burden on human and animal health. Among these, dengue virus is a prominent human health threat causing millions of infections every year worldwide, with no broadly effective or specific treatment. We previously showed that dengue virus infection results in a block in host protein synthesis, yet it remains a mystery how viral proteins are translated to support viral propagation. This is important because understanding how viruses hijack host resources can reveal a new Achilles' heel in the viral armour.Based on our results, we propose that dengue virus proteins are translated via a novel mechanism that uses a known cellular translation factor, eIF3, in a non-conventional manner to mediate translation. We also propose that this mechanism could help dengue virus escape detection by the host. Therefore, our objectives are to 1- characterize how eIF3 interacts with the viral RNA; 2- elucidate how this contributes to a new mechanism of translation and 3- establish how this mechanism competes with non-self detection of the viral RNA by the host. From this work we expect to advance our knowledge of how viruses take control of host resources to ensure viral proteins are made. This mechanism is novel, and we think it represents a new line of counterdefence evolved by viruses. Therefore, it can help identify new ways to inhibit virus replication and develop novel antiviral therapies for an important group of viruses. Understanding the fundamental mechanisms of gene regulation is important for virologists, but also for broader academic communities. It may also help us to appreciate better a basis of several pathologies, such as cancer or neurodegenerative diseases, that are linked to alternative translation mechanisms.