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Elife. 2019 Mar 7;8. pii: e43002. doi: 10.7554/eLife.43002.

Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness.

Author information

1
Department of Genetics, Harvard Medical School, Boston, United States.
2
Program in Chemical Biology, Harvard University, Cambridge, United States.
3
Department of Systems Biology, Harvard Medical School, Boston, United States.
4
Department of Molecular Biology, Princeton University, Princeton, United States.
5
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States.
6
Whitehead Institute for Biomedical Research, Cambridge, United States.
7
Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States.
8
Center for Physics of Evolving Systems, University of Chicago, Chicago, 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.

KEYWORDS:

Hsf1; S. cerevisiae; biochemistry; cell biology; chemical biology; protein aggregation; proteostasis; ribosome biogenesis; stress

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