Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness
- Harvard Medical School, United States
- Princeton University, United States
- Whitehead Institute for Biomedical Research, United States
Abstract
To achieve maximal growth, cells must manage a massive economy of ribosomal proteins (r-proteins) and RNAs (rRNAs) to produce thousands of ribosomes every minute. Although ribosomes are essential in all cells, natural disruptions to ribosome biogenesis lead to heterogeneous phenotypes. Here, we model these perturbations in Saccharomyces cerevisiae and show that challenges to ribosome biogenesis result in acute loss of proteostasis. Imbalances in the synthesis of r-proteins and rRNAs lead to the rapid aggregation of newly synthesized orphan r-proteins and compromise essential cellular processes, which cells alleviate by activating proteostasis genes. Exogenously bolstering the proteostasis network increases cellular fitness in the face of challenges to ribosome assembly, demonstrating the direct contribution of orphan r-proteins to cellular phenotypes. We propose that ribosome assembly is a key vulnerability of proteostasis maintenance in proliferating cells that may be compromised by diverse genetic, environmental, and xenobiotic perturbations that generate orphan r-proteins.
Data availability
All sequencing data have been deposited on Gene Expression Omnibus under accession number GSE114077.
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A risk-reward tradeoff of high ribosome production in proliferating cellsNCBI Gene Expression Omnibus, GSE114077.
Article and author information
Author details
L Stirling Churchman
Funding
National Institutes of Health (R01-HG007173)
- L Stirling Churchman
National Science Foundation (2013171680)
- Blake W Tye
National Institutes of Health (R01-GM117333)
- L Stirling Churchman
National Institutes of Health (R01-GM120122)
- Michael Springer
National Institutes of Health (R35-GM128813)
- Martin Wühr
Department of Energy, Labor and Economic Growth (DE-SC0018420)
- Martin Wühr
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Tye 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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Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness
eLife 8:e43002.
https://doi.org/10.7554/eLife.43002
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