Effects of RNA virus infection on stress granules, GW bodies and mRNP remodelling

为了应对环境压力，细胞重新编程其蛋白质合成机制，以便仅表达维持细胞活力所需的蛋白质。编码其他蛋白质的信使RNA（mRNA）从蛋白质合成的位点--多聚核糖体（polysome）重新定位，并积累在称为应激颗粒（SG）的结构中。SG的形成沿着蛋白质合成的一般停止。SG被认为是mRNA分类的位点，其中细胞决定mRNA是否将被保留直到条件改善，返回到多核糖体，或定向到GW体（GWB），在那里它被降解。病毒利用和操纵许多细胞过程以使其受益。许多病毒已经进化出选择性抑制细胞蛋白质合成而有利于病毒蛋白质合成的机制。病毒还必须破坏细胞对感染压力的保护性反应，以及由此导致的蛋白质合成的关闭。我们假设病毒已经进化出机制来破坏在应激反应中发生的mRNA分类和降解的正常过程，从而导致SG和GWB的组装和组成的变化。我们的初步工作支持我们的假设。在感染脊髓灰质炎病毒和与脊髓灰质炎病毒密切相关的病毒的细胞中，GW体分解并且SG不形成，即使TIA-1（从细胞核移动以形成SG的SG的蛋白质组分）确实从细胞核消失。因此，在感染这些病毒的细胞中不会发生对压力的正常反应。因此，我们研究的具体目标是（i）鉴定负责SG和GWB形成和功能变化的病毒蛋白，以及（ii）阐明病毒蛋白破坏SG和GWB的机制。我们还希望测试其他病毒家族成员对SG和GWB的影响。病毒已经进化出改变SG和/或GWB功能的机制这一概念是新颖的，我们的工作很可能鉴定出病毒蛋白和细胞蛋白之间以前未被认识到的分子相互作用，这些分子相互作用代表了抗病毒治疗的潜在新靶点。

In response to environmental stress, cells reprogram their protein synthesis machinery so that only those proteins required to maintain cell viability are expressed. Messenger RNAs (mRNAs) that code for other proteins are relocated from polysomes, the sites of protein synthesis, and accumulate in structures known as stress granules (SGs). The formation of SGs occurs along with a general shutdown of protein synthesis. SGs are believed to be sites of mRNA triage, where the cell decides if mRNA will be held until conditions improve, returned to polysomes, or directed to GW bodies (GWBs), where it is degraded. Viruses exploit and manipulate many cellular processes to their benefit. Many viruses have evolved mechanisms to selectively inhibit cellular protein synthesis in favour of viral protein synthesis. Viruses must also subvert the protective response of cells to the stress of an infection, and the resulting shutdown of protein synthesis. We hypothesize that viruses have evolved mechanisms to disrupt the normal processes of mRNA triage and degradation that occur in response to stress, leading to changes in the assembly and composition of SGs and GWBs. Our preliminary work supports our hypothesis. In cells infected with poliovirus, and viruses closely related to poliovirus, GW bodies disassemble and SGs do not form, even though TIA-1, a protein component of SGs that moves from the nucleus to form SGs, does disappear from the nucleus. Therefore, the normal response to stress does not occur in cells infected with these viruses. The specific objectives of our research, therefore, are (i) to identify viral proteins responsible for changes in SG and GWB formation and function, and (ii) to elucidate the mechanisms by which viral proteins disrupt SGs and GWBs. We also wish to test members of other virus families for their effects on SGs and GWBs. The concept that viruses have evolved mechanisms to alter SG and/or GWB function is novel and our work is likely to identify previously unrecognized molecular interactions between viral proteins and cellular proteins that represent potential new targets for antiviral therapies.