TY - JOUR
T1 - Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness
AU - Tye, Blake W.
AU - Commins, Nicoletta
AU - Ryazanova, Lillia V.
AU - Wühr, Martin
AU - Springer, Michael
AU - Pincus, David
AU - Churchman, L. Stirling
N1 - Funding Information:
We thank members of the Churchman lab, F Winston, R Kingston, and M Sonnett for helpful discussions; S Doris, E McShane, and C Patil for critical reading of the manuscript; and T Powers, F Hol-stege, V Denic, and D Gross for reagents. Microscopy was performed at the Nikon Imaging Center at Harvard Medical School and the WM Keck Microscopy Facility at the Whitehead Institute. RNA-seq library preparation and sequencing was performed at the Whitehead Institute and Biopolymers Facility at Harvard Medical School, respectively. This work was supported by the NIH (R01-HG007173 and R01-GM117333 to LSC, R01-GM120122 to MS, R35-GM128813 to MW), the DOE (DE-SC0018420 to MW), and the NSF (Graduate Research Fellowship to BWT).
Publisher Copyright:
© Tye et al.
PY - 2019/3
Y1 - 2019/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064579945&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064579945&partnerID=8YFLogxK
U2 - 10.7554/eLife.43002
DO - 10.7554/eLife.43002
M3 - Article
C2 - 30843788
AN - SCOPUS:85064579945
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e43002
ER -