在神经退行性病变中,过多的 STAU1 冷凝物会驱动 mTOR 翻译和自噬功能障碍。

IF 7.4 1区 生物学 Q1 CELL BIOLOGY Journal of Cell Biology Pub Date : 2024-08-05 Epub Date: 2024-06-24 DOI:10.1083/jcb.202311127
Ruiqian Zhao, Shijing Huang, Jingyu Li, Aihong Gu, Minjie Fu, Wei Hua, Ying Mao, Qun-Ying Lei, Boxun Lu, Wenyu Wen
{"title":"在神经退行性病变中,过多的 STAU1 冷凝物会驱动 mTOR 翻译和自噬功能障碍。","authors":"Ruiqian Zhao, Shijing Huang, Jingyu Li, Aihong Gu, Minjie Fu, Wei Hua, Ying Mao, Qun-Ying Lei, Boxun Lu, Wenyu Wen","doi":"10.1083/jcb.202311127","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.4000,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11194678/pdf/","citationCount":"0","resultStr":"{\"title\":\"Excessive STAU1 condensate drives mTOR translation and autophagy dysfunction in neurodegeneration.\",\"authors\":\"Ruiqian Zhao, Shijing Huang, Jingyu Li, Aihong Gu, Minjie Fu, Wei Hua, Ying Mao, Qun-Ying Lei, Boxun Lu, Wenyu Wen\",\"doi\":\"10.1083/jcb.202311127\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":15211,\"journal\":{\"name\":\"Journal of Cell Biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.4000,\"publicationDate\":\"2024-08-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11194678/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Cell Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1083/jcb.202311127\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/24 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Cell Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1083/jcb.202311127","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/24 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

双链 RNA 结合蛋白 Staufen1(STAU1)通过介导 RNA 代谢调控多种生理和病理事件。在小鼠模型的组织和神经退行性疾病患者的成纤维细胞中观察到了 STAU1 的过量存在,并伴随着 mTOR 信号转导的增强和自噬通量的减弱,但其潜在机制仍然难以捉摸。在这里,我们发现内源性 STAU1 在正常细胞系、肿瘤细胞系以及小鼠亨廷顿氏病基因敲除纹状体细胞中形成动态胞质凝聚物。STAU1凝聚物在其5'UTR处招募靶mRNA MTOR并促进其在体外和体内的翻译,因此STAU1凝聚物的形成增强会导致mTOR过度激活和自噬-溶酶体功能障碍。在神经退行性疾病的细胞模型中,干扰 STAU1 冷凝物可使 mTOR 水平恢复正常、改善自噬-溶酶体功能并减少病理蛋白的聚集。这些发现凸显了平衡相分离在生理过程中的重要性,表明调节 STAU1 冷凝物可能是缓解 STAU1 过量导致的神经退行性疾病进展的一种策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Excessive STAU1 condensate drives mTOR translation and autophagy dysfunction in neurodegeneration.

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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Cell Biology
Journal of Cell Biology 生物-细胞生物学
CiteScore
12.60
自引率
2.60%
发文量
213
审稿时长
1 months
期刊介绍: The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.
期刊最新文献
Arrayed CRISPRi library to suppress genes required for Schizosaccharomyces pombe viability. Postsynaptic BMP signaling regulates myonuclear properties in Drosophila larval muscles. Heterogeneity of late endosome/lysosomes shown by multiplexed DNA-PAINT imaging. Kinetochores grip microtubules with directionally asymmetric strength. Definition of phosphatidylinositol 4,5-bisphosphate distribution by freeze-fracture replica labeling.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1