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Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis

Author

Listed:
  • Kevin C. Stein

    (Stanford University)

  • Fabián Morales-Polanco

    (Stanford University)

  • Joris Lienden

    (Stanford University)

  • T. Kelly Rainbolt

    (Stanford University)

  • Judith Frydman

    (Stanford University
    Stanford University)

Abstract

Ageing is accompanied by a decline in cellular proteostasis, which underlies many age-related protein misfolding diseases1,2. Yet, how ageing impairs proteostasis remains unclear. As nascent polypeptides represent a substantial burden on the proteostasis network3, we hypothesized that altered translational efficiency during ageing could help to drive the collapse of proteostasis. Here we show that ageing alters the kinetics of translation elongation in both Caenorhabditis elegans and Saccharomyces cerevisiae. Ribosome pausing was exacerbated at specific positions in aged yeast and worms, including polybasic stretches, leading to increased ribosome collisions known to trigger ribosome-associated quality control (RQC)4–6. Notably, aged yeast cells exhibited impaired clearance and increased aggregation of RQC substrates, indicating that ageing overwhelms this pathway. Indeed, long-lived yeast mutants reduced age-dependent ribosome pausing, and extended lifespan correlated with greater flux through the RQC pathway. Further linking altered translation to proteostasis collapse, we found that nascent polypeptides exhibiting age-dependent ribosome pausing in C. elegans were strongly enriched among age-dependent protein aggregates. Notably, ageing increased the pausing and aggregation of many components of proteostasis, which could initiate a cycle of proteostasis collapse. We propose that increased ribosome pausing, leading to RQC overload and nascent polypeptide aggregation, critically contributes to proteostasis impairment and systemic decline during ageing.

Suggested Citation

  • Kevin C. Stein & Fabián Morales-Polanco & Joris Lienden & T. Kelly Rainbolt & Judith Frydman, 2022. "Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis," Nature, Nature, vol. 601(7894), pages 637-642, January.
  • Handle: RePEc:nat:nature:v:601:y:2022:i:7894:d:10.1038_s41586-021-04295-4
    DOI: 10.1038/s41586-021-04295-4
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    Cited by:

    1. Chisa Shiraishi & Akinobu Matsumoto & Kazuya Ichihara & Taishi Yamamoto & Takeshi Yokoyama & Taisuke Mizoo & Atsushi Hatano & Masaki Matsumoto & Yoshikazu Tanaka & Eriko Matsuura-Suzuki & Shintaro Iwa, 2023. "RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Yudong Fu & Fan Jiang & Xiao Zhang & Yingyi Pan & Rui Xu & Xiu Liang & Xiaofen Wu & Xingqiang Li & Kaixuan Lin & Ruona Shi & Xiaofei Zhang & Dominique Ferrandon & Jing Liu & Duanqing Pei & Jie Wang & , 2024. "Perturbation of METTL1-mediated tRNA N7- methylguanosine modification induces senescence and aging," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Kaushik Bhattacharya & Samarpan Maiti & Szabolcs Zahoran & Lorenz Weidenauer & Dina Hany & Diana Wider & Lilia Bernasconi & Manfredo Quadroni & Martine Collart & Didier Picard, 2022. "Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Bin Shao & Jiawei Yan & Jing Zhang & Lili Liu & Ye Chen & Allen R. Buskirk, 2024. "Riboformer: a deep learning framework for predicting context-dependent translation dynamics," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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