Department of Neurosurgery, Huashan Hospital, The Shanghai Key Laboratory of Medical Epigenetics, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
J Cell Biol. 2024 Aug 5;223(8). doi: 10.1083/jcb.202311127. Epub 2024 Jun 24.
The double-stranded RNA-binding protein Staufen1 (STAU1) regulates a variety of physiological and pathological events via mediating RNA metabolism. STAU1 overabundance was observed in tissues from mouse models and fibroblasts from patients with neurodegenerative diseases, accompanied by enhanced mTOR signaling and impaired autophagic flux, while the underlying mechanism remains elusive. Here, we find that endogenous STAU1 forms dynamic cytoplasmic condensate in normal and tumor cell lines, as well as in mouse Huntington's disease knockin striatal cells. STAU1 condensate recruits target mRNA MTOR at its 5'UTR and promotes its translation both in vitro and in vivo, and thus enhanced formation of STAU1 condensate leads to mTOR hyperactivation and autophagy-lysosome dysfunction. Interference of STAU1 condensate normalizes mTOR levels, ameliorates autophagy-lysosome function, and reduces aggregation of pathological proteins in cellular models of neurodegenerative diseases. These findings highlight the importance of balanced phase separation in physiological processes, suggesting that modulating STAU1 condensate may be a strategy to mitigate the progression of neurodegenerative diseases with STAU1 overabundance.
双链 RNA 结合蛋白 Staufen1（STAU1）通过调节 RNA 代谢来调控多种生理和病理事件。在神经退行性疾病患者的组织和成纤维细胞中观察到 STAU1 过度表达，伴随着增强的 mTOR 信号和受损的自噬流，但其潜在机制尚不清楚。在这里，我们发现内源性 STAU1 在正常和肿瘤细胞系以及小鼠亨廷顿病敲入纹状体细胞中形成动态细胞质凝聚物。STAU1 凝聚物在其 5'UTR 处募集靶 mRNA MTOR，并在体外和体内促进其翻译，因此增强的 STAU1 凝聚物形成导致 mTOR 过度激活和自噬溶酶体功能障碍。STAU1 凝聚物的干扰可使 mTOR 水平正常化，改善自噬溶酶体功能，并减少神经退行性疾病细胞模型中病理性蛋白的聚集。这些发现强调了平衡相分离在生理过程中的重要性，表明调节 STAU1 凝聚物可能是减轻 STAU1 过度表达的神经退行性疾病进展的一种策略。
