生物
精氨酸
核糖体生物发生
神经退行性变
毒性
生物发生
下调和上调
PI3K/AKT/mTOR通路
翻译(生物学)
核糖体
细胞生物学
蛋白质生物合成
生物化学
氨基酸
信号转导
信使核糖核酸
内科学
核糖核酸
基因
医学
疾病
作者
Oleksandra Sirozh,Anabel Sáez-Mas,Bomi Jung,Laura Sanchez‐Burgos,Eduardo Zarzuela,Sara Rodrigo-Perez,Iván Ventoso,Vanesa Lafarga,Óscar Fernández-Capetillo
出处
期刊:Molecular Cell
[Elsevier]
日期:2024-04-01
卷期号:84 (8): 1527-1540.e7
被引量:2
标识
DOI:10.1016/j.molcel.2024.02.031
摘要
Nucleolar stress (NS) has been associated with age-related diseases such as cancer or neurodegeneration. To investigate how NS triggers toxicity, we used (PR)n arginine-rich peptides present in some neurodegenerative diseases as inducers of this perturbation. We here reveal that whereas (PR)n expression leads to a decrease in translation, this occurs concomitant with an accumulation of free ribosomal (r) proteins. Conversely, (PR)n-resistant cells have lower rates of r-protein synthesis, and targeting ribosome biogenesis by mTOR inhibition or MYC depletion alleviates (PR)n toxicity in vitro. In mice, systemic expression of (PR)97 drives widespread NS and accelerated aging, which is alleviated by rapamycin. Notably, the generalized accumulation of orphan r-proteins is a common outcome of chemical or genetic perturbations that induce NS. Together, our study presents a general model to explain how NS induces cellular toxicity and provides in vivo evidence supporting a role for NS as a driver of aging in mammals.
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