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.

核仁应激 (NS) 与癌症或神经退行性疾病等年龄相关疾病有关。为了研究 NS 如何引发毒性，我们使用一些神经退行性疾病中存在的 (PR)n 富含精氨酸的肽作为这种扰动的诱导剂。我们在此揭示，虽然 (PR)n 表达导致翻译减少，但这种情况伴随着游离核糖体 (r) 蛋白的积累而发生。相反，(PR)n 抗性细胞的 r 蛋白合成率较低，通过抑制 mTOR 或消除 MYC 来靶向核糖体生物合成可减轻 (PR)n 的体外毒性。在小鼠中，(PR) ₉₇的全身表达会导致广泛的 NS 并加速衰老，雷帕霉素可以缓解这种情况。值得注意的是，孤儿 r 蛋白的普遍积累是诱发 NS 的化学或遗传扰动的常见结果。总之，我们的研究提出了一个通用模型来解释 NS 如何诱导细胞毒性，并提供了支持 NS 作为哺乳动物衰老驱动因素的体内证据。