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Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness.

eLife | 2019

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.

Pubmed ID: 30843788 RIS Download

Associated grants

  • Agency: NIH HHS, United States
    Id: R01-HG007173
  • Agency: NIH HHS, United States
    Id: R01-GM120122
  • Agency: Department of Energy, Labor and Economic Growth, International
    Id: DE-SC0018420
  • Agency: NIH HHS, United States
    Id: R01-GM117333
  • Agency: National Science Foundation, International
    Id: 2013171680
  • Agency: NIGMS NIH HHS, United States
    Id: R35 GM128813
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM120122
  • Agency: NIH HHS, United States
    Id: R35-GM128813
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM117333
  • Agency: NHGRI NIH HHS, United States
    Id: R01 HG007173

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