Increasing cell size remodels the proteome and promotes senescence

Lanz, Michael; Zatulovskiy, Evgeny; Swaffer, Matthew P.; Zhang, Lichao; Ilerten, Ilayda; Zhang, Shuyuan; You, Dong Shin; Marinov, Georgi K.; McAlpine, Patrick L.; Elias, Joshua E.; Skotheim, Jan M.

doi:10.1016/j.molcel.2022.07.017

Cited by 120 publications

(163 citation statements)

References 66 publications

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“…The importance of cell size is reflected in its uniformity within any given cell type. Deviations from a typical size are often associated with disease states, such cancer and aging ( Ginzberg et al, 2015 ; Li et al, 2015 ; Nguyen et al, 2016 ; Neurohr et al, 2019 ; Zatulovskiy and Skotheim, 2020 ; Cheng et al, 2021 ; Lengefeld et al, 2021 ; Lanz et al, 2022 ; Sandlin, 2022 ). To avoid such problematic disease states, eukaryotic cells rely on dedicated mechanisms that correct for deviations from their target cell size ( Ginzberg et al, 2015 ; Cadart et al, 2018 ; Ginzberg et al, 2018 ; Liu et al, 2018 ; Zatulovskiy et al, 2020 ; Zatulovskiy and Skotheim, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…The relationship between cell size and cell physiology is apparent from size-dependent changes to the proteome. While most protein concentrations remain fairly constant as cells grow larger (protein amounts scale in proportion to cell size), many others increase (superscaling proteins) or decrease (subscaling proteins) in concentration ( Chen et al, 2020 ; Cheng et al, 2021 ; Claude et al, 2021 ; Lanz et al, 2022 ) ( Figure 1A ). Although a small change in a single protein’s concentration may not substantially affect cell physiology, the cumulative effect of thousands of such changes could account for profound changes in cell physiology.…”

Section: Introductionmentioning

confidence: 99%

“…Although a small change in a single protein’s concentration may not substantially affect cell physiology, the cumulative effect of thousands of such changes could account for profound changes in cell physiology. For example, recent work shows that excessively large cell size promotes senescence ( Demidenko and Blagosklonny, 2008 ; Neurohr et al, 2019 ; Lengefeld et al, 2021 ; Wilson et al, 2021 ; Crozier et al, 2022 ; Lanz et al, 2022 ). Thus, while differential size scaling of protein concentrations likely has important implications for cell physiology, the mechanistic origins of such size scaling remain unknown.…”

Section: Introductionmentioning

confidence: 99%

“…(F-H) Same experiment performed in (C–E) but measuring the protein synthesis rates in populations of RPE-1 cells with different ploidies. To generate tetraploid and octoploid cells, the cytokinesis was partially inhibited in RPE-1 cells using the Aurora kinase B inhibitor barasertib (100 nM, 48 h) ( Mu et al, 2020 ; Lanz et al, 2022 ), then 2C, 4C, and 8C were then gated using flow cytometry (F) . The overall protein synthesis rate (G) and the protein synthesis rate per unit volume (H) were plotted against the SSC-A, a proxy for cell volume.…”

Section: Introductionmentioning

confidence: 99%

“…One possibility for how cell size drives changes in protein concentrations would be that this is an indirect effect through the cell’s protein synthesis rate per unit volume (hereby referred to as growth rate), which decreases in larger cells ( Cadart et al, 2018 ; Neurohr et al, 2019 ; Liu et al, 2022 ) ( Figure 1B ). There seems to be a limit to the size range of effective biosynthesis, with larger cells exhibiting a loss of mitochondrial membrane potential ( Miettinen and Björklund, 2016 ) and reduced proliferative capacity ( Demidenko and Blagosklonny, 2008 ; Cheng et al, 2021 ; Lengefeld et al, 2021 ; Wilson et al, 2021 ; Lanz et al, 2022 ). As cells get larger, their growth becomes less efficient, and this may affect the concentrations of diverse sets of proteins.…”

Section: Introductionmentioning

confidence: 99%

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Delineation of proteome changes driven by cell size and growth rate

Zatulovskiy

Lanz

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Increasing cell size drives changes to the proteome, which affects cell physiology. As cell size increases, some proteins become more concentrated while others are diluted. As a result, the state of the cell changes continuously with increasing size. In addition to these proteomic changes, large cells have a lower growth rate (protein synthesis rate per unit volume). That both the cell’s proteome and growth rate change with cell size suggests they may be interdependent. To test this, we used quantitative mass spectrometry to measure how the proteome changes in response to the mTOR inhibitor rapamycin, which decreases the cellular growth rate and has only a minimal effect on cell size. We found that large cell size and mTOR inhibition, both of which lower the growth rate of a cell, remodel the proteome in similar ways. This suggests that many of the effects of cell size are mediated by the size-dependent slowdown of the cellular growth rate. For example, the previously reported size-dependent expression of some senescence markers could reflect a cell’s declining growth rate rather than its size per se. In contrast, histones and other chromatin components are diluted in large cells independently of the growth rate, likely so that they remain in proportion with the genome. Finally, size-dependent changes to the cell’s growth rate and proteome composition are still apparent in cells continually exposed to a saturating dose of rapamycin, which indicates that cell size can affect the proteome independently of mTORC1 signaling. Taken together, our results clarify the dependencies between cell size, growth, mTOR activity, and the proteome remodeling that ultimately controls many aspects of cell physiology.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Delineation of proteome changes driven by cell size and growth rate

Zatulovskiy

Lanz

Zhang

et al. 2022

Front. Cell Dev. Biol.

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DDR2 signaling and mechanosensing orchestrate neuroblastoma cell fate through different transcriptome mechanisms

Vessella,

Xiang,

Xiao

et al. 2024

FEBS Open Bio

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The extracellular matrix (ECM) regulates carcinogenesis by interacting with cancer cells via cell surface receptors. Discoidin Domain Receptor 2 (DDR2) is a collagen‐activated receptor implicated in cell survival, growth, and differentiation. Dysregulated DDR2 expression has been identified in various cancer types, making it as a promising therapeutic target. Additionally, cancer cells exhibit mechanosensing abilities, detecting changes in ECM stiffness, which is particularly important for carcinogenesis given the observed ECM stiffening in numerous cancer types. Despite these, whether collagen‐activated DDR2 signaling and ECM stiffness‐induced mechanosensing exert similar effects on cancer cell behavior and whether they operate through analogous mechanisms remain elusive. To address these questions, we performed bulk RNA sequencing (RNA‐seq) on human SH‐SY5Y neuroblastoma cells cultured on collagen‐coated substrates. Our results show that DDR2 downregulation induces significant changes in the cell transcriptome, with changes in expression of 15% of the genome, specifically affecting the genes associated with cell division and differentiation. We validated the RNA‐seq results by showing that DDR2 knockdown redirects the cell fate from proliferation to senescence. Like DDR2 knockdown, increasing substrate stiffness diminishes cell proliferation. Surprisingly, RNA‐seq indicates that substrate stiffness has no detectable effect on the transcriptome. Furthermore, DDR2 knockdown influences cellular responses to substrate stiffness changes, highlighting a crosstalk between these two ECM‐induced signaling pathways. Based on our results, we propose that the ECM could activate DDR2 signaling and mechanosensing in cancer cells to orchestrate their cell fate through distinct mechanisms, with or without involving gene expression, thus providing novel mechanistic insights into cancer progression.

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The Matrix Protein Tropoelastin Prolongs Mesenchymal Stromal Cell Vitality and Delays Senescence During Replicative Aging

Lee,

Al Halawani,

Teo

et al. 2024

Advanced Science

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Cellular senescence leads to the functional decline of regenerative cells such as mesenchymal stromal/stem cells (MSCs), which gives rise to chronic conditions and contributes to poor cell therapy outcomes. Aging tissues are associated with extracellular matrix (ECM) dysregulation, including loss of elastin. However, the role of the ECM in modulating senescence is underexplored. In this work, it is shown that tropoelastin, the soluble elastin precursor, is not only a marker of young MSCs but also actively preserves cell fitness and delays senescence during replicative aging. MSCs briefly exposed to tropoelastin exhibit upregulation of proliferative genes and concurrent downregulation of senescence genes. The seno‐protective benefits of tropoelastin persist during continuous, long‐term MSC culture, and significantly extend the MSC replicative lifespan. Tropoelastin‐expanded MSCs further maintain youth‐associated phenotype and function compared to age‐matched controls, including preserved clonogenic potential, minimal senescence‐associated beta‐galactosidase activity, maintained cell sizes, reduced expression of senescence markers, suppressed secretion of senescence‐associated factors, and increased production of youth‐associated proteins. This work points to the utility of exogenously‐supplemented tropoelastin for manufacturing MSCs that robustly maintain regenerative potential with age. It further reveals the active role of classical structural ECM proteins in driving cellular age‐associated fitness, potentially leading to future interventions for aging‐related pathologies.

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Increasing cell size remodels the proteome and promotes senescence

Cited by 120 publications

References 66 publications

Delineation of proteome changes driven by cell size and growth rate

Delineation of proteome changes driven by cell size and growth rate

DDR2 signaling and mechanosensing orchestrate neuroblastoma cell fate through different transcriptome mechanisms

The Matrix Protein Tropoelastin Prolongs Mesenchymal Stromal Cell Vitality and Delays Senescence During Replicative Aging

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