Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis

Ageing is accompanied by a decline in cellular proteostasis, which underlies many age-related protein misfolding diseases 1 , 2 . Yet, how ageing impairs proteostasis remains unclear. As nascent polypeptides represent a substantial burden on the proteostasis network 3 , we hypothesized that altered...

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Vydáno v:Nature (London) Ročník 601; číslo 7894; s. 637 - 642
Hlavní autoři: Stein, Kevin C., Morales-Polanco, Fabián, van der Lienden, Joris, Rainbolt, T. Kelly, Frydman, Judith
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 27.01.2022
Nature Publishing Group
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Age
Agglomeration
Aging
Amino acids
Animals
Caenorhabditis elegans - metabolism
Elongation
Humanities and Social Sciences
Life span
multidisciplinary
Peptides - metabolism
Polypeptides
Protein Biosynthesis
Protein folding
Proteins
Proteostasis
Quality control
Ribosomes - metabolism
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae Proteins - metabolism
Science
Science (multidisciplinary)
Substrates
Translation
Translation elongation
Ubiquitin-Protein Ligases - metabolism
Yeast
ISSN:0028-0836, 1476-4687, 1476-4687
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Shrnutí:Ageing is accompanied by a decline in cellular proteostasis, which underlies many age-related protein misfolding diseases 1 , 2 . Yet, how ageing impairs proteostasis remains unclear. As nascent polypeptides represent a substantial burden on the proteostasis network 3 , 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. Ageing alters the kinetics of translation elongation in both Caenorhabditis elegans and Saccharomyces cerevisiae .
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Author contributions K.C.S. and J.F. designed the study. K.C.S. performed all experiments and computational analyses, with assistance from F.M-P., JL., and T.K.R. in carrying out the yeast reporter immunoblot and microscopy experiments. K.C.S. and J.F. wrote the manuscript with input from all authors.
ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-021-04295-4