Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness.

TitleProteotoxicity from aberrant ribosome biogenesis compromises cell fitness.
Publication TypeJournal Article
Year of Publication2019
AuthorsTye, BW, Commins, N, Ryazanova, LV, Wühr, M, Springer, M, Pincus, D, L Churchman, S
JournalElife
Volume8
Date Published2019 Mar 07
ISSN2050-084X
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.

DOI10.7554/eLife.43002
Alternate JournalElife
PubMed ID30843788
PubMed Central IDPMC6453566
Grant ListR01-HG007173 / / National Institutes of Health /
R01-GM120122 / / National Institutes of Health /
DE-SC0018420 / / Department of Energy, Labor and Economic Growth /
R01-GM117333 / / National Institutes of Health /
2013171680 / / National Science Foundation /
R35 GM128813 / GM / NIGMS NIH HHS / United States
R01 GM120122 / GM / NIGMS NIH HHS / United States
R35-GM128813 / / National Institutes of Health /
R01 GM117333 / GM / NIGMS NIH HHS / United States
R01 HG007173 / HG / NHGRI NIH HHS / United States