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
Date Published2019 03 07
KeywordsMicrobial Viability, Organelle Biogenesis, Protein Aggregation, Pathological, Protein Biosynthesis, Proteostasis, Ribosomal Proteins, Ribosomes, RNA, Ribosomal, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins

<p>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.</p>

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