RNA应激颗粒的内平衡调控机制

RNA应激颗粒是在胞质中由mRNA和蛋白质互相结合、通过液液分离的方式形成的无膜结构作为mRNA的暂时存储单元，以应对机体的不同发育阶段或者氧化应激等造成的压力。这种颗粒结构处于不断的聚合和解聚的动态平衡中，且持续地与胞质进行内容物的交换。在一些神经退行性疾病如ALS/FTD中，突变蛋白结合RNA形成类固态的病理性聚集而无法解聚，造成蛋白质合成和RNA代谢异常。本项目通过生化、细胞生物学、体外液液分相等手段，解析蛋白质质量控制系统如何维持生理性RNA应激颗粒的内平衡，寻找参与RNA应激颗粒自噬降解的关键蛋白分子和特异性自噬受体；并利用C9orf72和FUS突变体构建细胞和小鼠ALS模型，系统地鉴定病理性RNA颗粒的自噬降解分子机理。本项目将为研究无膜细胞器的自噬依赖的蛋白质质量控制机制提供系统性的信息，并为ALS/FTD等神经退行性疾病治疗药物的研发提供理论基础。

RNA stress granules are assemblies of mRNAs and proteins when translation initiation is inhibited under stress. They are fluid-like compartments formed by liquid-liquid phase separation (LLPS), and the composition of granules is highly dynamic in cells. However, in some neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), the pathological mutant proteins bind RNA to form solid-like aggregates which cannot be disassembled by themselves. Studies suggest that these aberrant granules are cleaned up by the autophagy pathway. Nevertheless, the detail mechanism of the degradation process is not clear. This proposal is aimed to elucidate the mechanism of how the protein quality control system regulates the dynamics of RNA stress granules to keep cellular homeostasis. We will apply multiple strategies including screening the E3 ligases functioning in RNA granule assembly/disassembly, identifying specific autophagy receptors in RNA granule degradation process, and building cellular and mouse ALS models to explore the autophagy-dependent degradation of pathological RNA granules. We will combine biochemistry, cellular biology and in vitro LLPS reconstitution approaches to investigate the mechanisms mentioned above.