Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness

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 mode...

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Bibliographic Details
Published in:eLife 2019-03, Vol.8
Main Authors: Tye, Blake W, Commins, Nicoletta, Ryazanova, Lillia V, Wühr, Martin, Springer, Michael, Pincus, David, Churchman, L Stirling
Format: Article
Language:English
Subjects:
BASIC BIOLOGICAL SCIENCES
Biochemistry and Chemical Biology
Biology
Biosynthesis
Cell Biology
Cells (Biology)
Gene expression
Genetic aspects
Genetic diversity
Genomics
Hsf1
Microbial Viability
Mutation
Observations
Organelle Biogenesis
Phenotypes
Physiological aspects
protein aggregation
Protein Aggregation, Pathological
Protein Biosynthesis
Protein synthesis
Proteins
Proteostasis
Reproductive fitness
Ribosomal proteins
Ribosomal Proteins - biosynthesis
Ribosomal Proteins - toxicity
ribosome biogenesis
Ribosomes
Ribosomes - metabolism
RNA, Ribosomal - biosynthesis
Saccharomyces cerevisiae - growth & development
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - biosynthesis
Saccharomyces cerevisiae Proteins - toxicity
stress
Yeast
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Summary: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 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.43002