Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis
Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/75393 |
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| author | Shixuan Liu Ceryl Tan Chloe Melo-Gavin Miriam B Ginzberg Ron Blutrich Nish Patel Michael Rape Kevin G Mark Ran Kafri |
| author_facet | Shixuan Liu Ceryl Tan Chloe Melo-Gavin Miriam B Ginzberg Ron Blutrich Nish Patel Michael Rape Kevin G Mark Ran Kafri |
| author_sort | Shixuan Liu |
| collection | DOAJ |
| description | Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018). While we previously identified the p38 MAPK pathway as a key regulator of the mammalian cell size checkpoint (Liu et al., 2018), the mechanism of size-dependent growth rate regulation has remained elusive. Here, we quantified global rates of protein synthesis and degradation in cells of varying sizes, both under unperturbed conditions and in response to perturbations that trigger size-dependent compensatory growth slowdown. We found that protein synthesis rates scale proportionally with cell size across cell cycle stages and experimental conditions. In contrast, oversized cells that undergo compensatory growth slowdown exhibit a superlinear increase in proteasome-mediated protein degradation, with accelerated protein turnover per unit mass, suggesting activation of the proteasomal degradation pathway. Both nascent and long-lived proteins contribute to the elevated protein degradation during compensatory growth slowdown, with long-lived proteins playing a crucial role at the G1/S transition. Notably, large G1/S cells exhibit particularly high efficiency in protein degradation, surpassing that of similarly sized or larger cells in S and G2, coinciding with the timing of the most stringent size control in animal cells. These results collectively suggest that oversized cells reduce their growth efficiency by activating global proteasome-mediated protein degradation to promote cell size homeostasis. |
| format | Article |
| id | doaj-art-e83d854dc5f542ce95cf899c9e734eba |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-e83d854dc5f542ce95cf899c9e734eba2025-02-10T15:12:04ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011410.7554/eLife.75393Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasisShixuan Liu0https://orcid.org/0000-0003-4972-415XCeryl Tan1https://orcid.org/0000-0002-9010-9039Chloe Melo-Gavin2Miriam B Ginzberg3Ron Blutrich4Nish Patel5Michael Rape6https://orcid.org/0000-0003-4849-6343Kevin G Mark7Ran Kafri8https://orcid.org/0000-0002-9656-0189Department of Molecular Genetics, University of Toronto, Toronto, Canada; Cell Biology, The Hospital for Sick Children, Toronto, Toronto, Canada; Department of Chemical and Systems Biology, Stanford University, Stanford, United StatesDepartment of Molecular Genetics, University of Toronto, Toronto, Canada; Cell Biology, The Hospital for Sick Children, Toronto, Toronto, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, Canada; Cell Biology, The Hospital for Sick Children, Toronto, Toronto, CanadaCell Biology, The Hospital for Sick Children, Toronto, Toronto, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, Canada; Cell Biology, The Hospital for Sick Children, Toronto, Toronto, CanadaCell Biology, The Hospital for Sick Children, Toronto, Toronto, CanadaDepartment of Molecular Cell Biology, University of California at Berkeley, Berkeley, United StatesDepartment of Molecular Cell Biology, University of California at Berkeley, Berkeley, United States; Department of Cell Biology, UT Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Genetics, University of Toronto, Toronto, Canada; Cell Biology, The Hospital for Sick Children, Toronto, Toronto, CanadaProliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018). While we previously identified the p38 MAPK pathway as a key regulator of the mammalian cell size checkpoint (Liu et al., 2018), the mechanism of size-dependent growth rate regulation has remained elusive. Here, we quantified global rates of protein synthesis and degradation in cells of varying sizes, both under unperturbed conditions and in response to perturbations that trigger size-dependent compensatory growth slowdown. We found that protein synthesis rates scale proportionally with cell size across cell cycle stages and experimental conditions. In contrast, oversized cells that undergo compensatory growth slowdown exhibit a superlinear increase in proteasome-mediated protein degradation, with accelerated protein turnover per unit mass, suggesting activation of the proteasomal degradation pathway. Both nascent and long-lived proteins contribute to the elevated protein degradation during compensatory growth slowdown, with long-lived proteins playing a crucial role at the G1/S transition. Notably, large G1/S cells exhibit particularly high efficiency in protein degradation, surpassing that of similarly sized or larger cells in S and G2, coinciding with the timing of the most stringent size control in animal cells. These results collectively suggest that oversized cells reduce their growth efficiency by activating global proteasome-mediated protein degradation to promote cell size homeostasis.https://elifesciences.org/articles/75393cell sizecell size homeostasisgrowth rate compensationproteasome-mediated protein degradation |
| spellingShingle | Shixuan Liu Ceryl Tan Chloe Melo-Gavin Miriam B Ginzberg Ron Blutrich Nish Patel Michael Rape Kevin G Mark Ran Kafri Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis eLife cell size cell size homeostasis growth rate compensation proteasome-mediated protein degradation |
| title | Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis |
| title_full | Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis |
| title_fullStr | Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis |
| title_full_unstemmed | Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis |
| title_short | Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis |
| title_sort | oversized cells activate global proteasome mediated protein degradation to maintain cell size homeostasis |
| topic | cell size cell size homeostasis growth rate compensation proteasome-mediated protein degradation |
| url | https://elifesciences.org/articles/75393 |
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