Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates ageing in mice

biorxiv(2023)

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摘要
Nucleolar stress (NS) kills cells through p53-dependent and independent manners. To investigate the mechanisms of p53-indendendent toxicity, we here used (PR)n arginine-rich peptides as inducers of NS, which are found in patients of certain neurodegenerative diseases. Although these peptides accumulate at nucleoli and generate NS, how this translates to cellular toxicity is poorly understood. We here reveal that whereas (PR)n expression leads to an overall decrease in protein abundance, this occurs concomitant to an accumulation of free ribosomal (r) proteins in the cytoplasm, a hallmark of ribosomopathies. Conversely, cells with acquired resistance to (PR)n peptides present a global downregulation of r-proteins and low levels of mTOR signaling. In mice, systemic expression of (PR)97 drives widespread NS and accelerated ageing, associated to an increased expression of r-proteins and mTOR hyperactivation. Furthermore, the reduced lifespan of (PR)97-expressing mice is alleviated by rapamycin. Importantly, we show that the generalised accumulation of free r-proteins is a common outcome in response to chemical or genetic perturbations that trigger NS, such as Actinomycin D, TIF-IA depletion, or the expression of mutant HMGB1 variants recently associated to rare human diseases. Together, our study presents in vivo evidence supporting the role of NS as a driver of ageing in mammals, and provides a general framework to explain the mechanisms behind p53-independent cell toxicity caused by NS. ### Competing Interest Statement The authors have declared no competing interest.
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