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

为了应对环境压力，细胞重新编程它们的蛋白质合成机制，以便只表达那些维持细胞活力所需的蛋白质。编码其他蛋白质的信使RNA(MRNAs)从蛋白质合成的多聚体重新定位，并在称为应激颗粒(SGS)的结构中积累。SGS的形成伴随着蛋白质合成的全面停止。SGS被认为是mRNA分流的部位，在那里细胞决定是否将mRNA保留到条件改善，返回到多聚体，或者定向到GW小体(GWB)，在那里它被降解。病毒利用和操纵许多细胞过程，使它们受益。许多病毒已经进化出选择性地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停止。我们假设，病毒已经进化出机制，扰乱了应激反应中发生的mRNA分流和降解的正常过程，导致SGS和GWB的组装和组成发生变化。我们的初步工作支持了我们的假设。在感染了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小体解体，SGS不形成，即使SGS的蛋白质成分TIA-1从细胞核中移动形成SGS确实从细胞核中消失。因此，感染了这些病毒的细胞不会出现正常的应激反应。因此，我们研究的具体目标是(I)确定导致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SGS和GWB的机制。我们还希望测试其他病毒家族的成员对SGS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，我们的工作可能会识别以前未知的病毒蛋白和细胞蛋白之间的分子相互作用，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.