Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with challenges to proteostasis
- University of California, San Diego, United States
Abstract
Chromatin instability and protein homeostasis (proteostasis) stress are two well-established hallmarks of aging, which have been considered largely independent of each other. Using microfluidics and single-cell imaging approaches, we observed that, during the replicative aging of S. cerevisiae, a challenge to proteostasis occurs specifically in the fraction of cells with decreased stability within the ribosomal DNA (rDNA). A screen of 170 yeast RNA-binding proteins identified ribosomal RNA (rRNA)-binding proteins as the most enriched group that aggregate upon a decrease in rDNA stability induced by inhibition of a conserved lysine deacetylase Sir2. Further, loss of rDNA stability induces age-dependent aggregation of rRNA-binding proteins through aberrant overproduction of rRNAs. These aggregates contribute to age-induced proteostasis decline and limit cellular lifespan. Our findings reveal a mechanism underlying the interconnection between chromatin instability and proteostasis stress and highlight the importance of cell-to-cell variability in aging processes.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source data have been provided for Figure 2.
Article and author information
Author details
Funding
National Institutes of Health (R01AG056440)
- Lev S Tsimring
- Lorraine Pillus
- Jeff Hasty
- Nan Hao
National Institutes of Health (R01GM111458)
- Nan Hao
National Institutes of Health (R01AG068112)
- Nan Hao
National Institutes of Health (T32GM007240)
- Julie Paxman
National Science Foundation (MCB1716841)
- Lorraine Pillus
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Martin Sebastian Denzel, Altos Labs, United Kingdom
Version history
- Received: November 30, 2021
- Preprint posted: December 7, 2021 (view preprint)
- Accepted: October 3, 2022
- Accepted Manuscript published: October 4, 2022 (version 1)
- Version of Record published: October 18, 2022 (version 2)
Copyright
© 2022, Paxman et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with challenges to proteostasis
eLife 11:e75978.
https://doi.org/10.7554/eLife.75978
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