Cellular perception of growth rate and the mechanistic origin of bacterial growth law

Wu, Chenhao; Balakrishnan, Rohan; Braniff, Nathan; Mori, Matteo; Manzanarez, Gabriel; Zhang, Zhongge; Hwa, Terence

doi:10.1073/pnas.2201585119

Cited by 54 publications

(124 citation statements)

References 83 publications

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“…In chemostat experiments where growth is limited by nutrient restriction, the abundance of RP and RiBi genes correlates with growth rate, consistent with one set of long-standing models of growth limitations in bacteria (74)(75)(76)(77)(78)(79). However, other seminal studies focusing on stress conditions suggest that growth during stress is not limited by ribosome production (58,(80)(81)(82)(83)(84). Our results show clearly that expression of RP and RiBi genes . In contrast, the EWY55 strain that recovers anaerobic growth on xylose shows higher expression of ribosome-related genes, perhaps supporting rapid division.…”

Section: Discussionsupporting

confidence: 87%

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth inSaccharomyces cerevisiae

Wagner

Nightingale

Jen

et al. 2022

Preprint

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Organisms have evolved elaborate physiological pathways that regulate growth, proliferation, metabolism, and stress response. These pathways must be properly coordinated to elicit the appropriate response to an ever-changing environment. While individual pathways have been well studied in a variety of model systems, there remains much to uncover about how pathways are integrated to produce systemic changes in a cell, especially in dynamic conditions. We previously showed that deletion of Protein Kinase A (PKA) regulatory subunit BCY1 can decouple growth and metabolism in Saccharomyces cerevisiae engineered for anaerobic xylose fermentation, allowing for robust fermentation in the absence of division. This provides an opportunity to understand how PKA signaling normally coordinates these processes. Here, we integrated transcriptomic, lipidomic, and phosphor-proteomic responses upon a glucose to xylose shift across a series of strains with different genetic mutations promoting either coupled or decoupled xylose-dependent growth and metabolism. Together, results suggested that defects in lipid homeostasis limit growth in the bcy1Δ strain despite robust metabolism. To further understand this mechanism, we performed adaptive laboratory evolutions to re-evolve coupled growth and metabolism in the bcy1Δ parental strain. Genetic mutations in PKA subunit TPK1 and lipid regulator OPI1, among other genes underscored a role for lipid homeostasis, which was further supported by evolved changes in lipid profiles and gene expression. We suggest several models for how cells coordinate growth, metabolism, and other responses in budding yeast and how restructuring these processes enables anaerobic xylose utilization.

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Section: Discussionsupporting

confidence: 87%

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth inSaccharomyces cerevisiae

Wagner

Nightingale

Jen

et al. 2022

Preprint

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“…In the case of NaCl, the limiting factor is unlikely to be ribosomes: we previously showed that this yeast strain exposed to the same dose of NaCl removes a population of ribosomes from the translating pool immediately after stress ( Ho et al, 2018 ). This is consistent with bacterial models of growth regulation, in which cells preserve some ribosomes for later stress acclimation (also indicating that growth rate under these conditions is not limited by ribosome availability) ( Mori et al, 2017 ; Kim et al, 2018 ; Korem Kohanim et al, 2018 ; Remigi et al, 2019 ; Wu et al, 2022 ). Evidence from bacteria and incidental results in yeast suggest that other features related to translation elongation may limit cell growth in this situation ( Dai et al, 2018 ; Ho et al, 2018 ; Wu et al, 2022 ), a limitation that may be alleviated by removing some ribosomes from the translating pool.…”

Section: Discussionsupporting

confidence: 87%

“…This is consistent with bacterial models of growth regulation, in which cells preserve some ribosomes for later stress acclimation (also indicating that growth rate under these conditions is not limited by ribosome availability) ( Mori et al, 2017 ; Kim et al, 2018 ; Korem Kohanim et al, 2018 ; Remigi et al, 2019 ; Wu et al, 2022 ). Evidence from bacteria and incidental results in yeast suggest that other features related to translation elongation may limit cell growth in this situation ( Dai et al, 2018 ; Ho et al, 2018 ; Wu et al, 2022 ), a limitation that may be alleviated by removing some ribosomes from the translating pool. How all of this fits into broader cellular states is discussed below.…”

Section: Discussionsupporting

confidence: 87%

Modeling single-cell phenotypes links yeast stress acclimation to transcriptional repression and pre-stress cellular states

Bergen

Kocik

Hose

et al. 2022

eLife

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Stress defense and cell growth are inversely related in bulk culture analyses; however, these studies miss substantial cell-to-cell heterogeneity, thus obscuring true phenotypic relationships. Here, we devised a microfluidics system to characterize multiple phenotypes in single yeast cells over time before, during, and after salt stress. The system measured cell and colony size, growth rate, and cell-cycle phase along with nuclear trans-localization of two transcription factors: stress-activated Msn2 that regulates defense genes and Dot6 that represses ribosome biogenesis genes during an active stress response. By tracking cells dynamically, we discovered unexpected discordance between Msn2 and Dot6 behavior that revealed subpopulations of cells with distinct growth properties. Surprisingly, post-stress growth recovery was positively corelated with activation of the Dot6 repressor. In contrast, cells lacking Dot6 displayed slower growth acclimation, even though they grow normally in the absence of stress. We show that wild-type cells with a larger Dot6 response display faster production of Msn2-regulated Ctt1 protein, separable from the contribution of Msn2. These results are consistent with the model that transcriptional repression during acute stress in yeast provides a protective response, likely by redirecting translational capacity to induced transcripts.

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“…Mechanistically, this regulation of ribosome expression is carried out by the signaling molecule guanosine tetraphosphate (ppGpp). ppGpp is synthesized when charged tRNA levels are low [35, 36]. As charged tRNA abundance is proportional to amino acid levels, ppGpp thus indirectly acts as a sensor of the amino acid pool.…”

Section: Resultsmentioning

confidence: 99%

“…As a result, amino acid abundance is inversely proportional to ppGpp concentration, such that [ppGpp] ∝ 1/ a . In response to decreased amino acid levels, ppGpp levels increase and repress rRNA expression [35, 36]. Free ribosomal proteins, which can no longer bind rRNA, bind to their own mRNA and suppress additional ribosome translation [37].…”

Section: Resultsmentioning

confidence: 99%

Dynamic trade-offs between biomass accumulation and division determine bacterial cell size and proteome in fluctuating nutrient environments

Banerjee

Kratz

2022

Preprint

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Bacteria dynamically regulate cell size and growth rate to thrive in changing environments. While much work has been done to characterize bacterial growth physiology and cell size control during steady-state exponential growth, a quantitative understanding of how bacteria dynamically regulate cell size and growth in time-varying nutrient environments is lacking. Here we develop a dynamic coarse-grained proteome sector model which connects growth rate and division control to proteome allocation in time-varying environments in both exponential and stationary phase. In such environments, growth rate and size control is governed by trade-offs between prioritization of biomass accumulation or division, and results in the uncoupling of single-cell growth rate from population growth rate out of steady-state. Specifically, our model predicts that cells transiently prioritize ribosome production, and thus biomass accumulation, over production of division machinery during nutrient upshift, explaining experimentally observed size control behaviors. Strikingly, our model predicts the opposite behavior during downshift, namely that bacteria temporarily prioritize division over growth, despite needing to upregulate costly division machinery and increasing population size when nutrients are scarce. Importantly, when bacteria are subjected to pulsatile nutrient concentration, we find that cells exhibit a transient memory of the previous metabolic state due to the slow dynamics of proteome reallocation. This phenotypic memory allows for faster adaptation back to previously-seen environments when nutrient fluctuations are short-lived.

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Cellular perception of growth rate and the mechanistic origin of bacterial growth law

Cited by 54 publications

References 83 publications

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth inSaccharomyces cerevisiae

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth inSaccharomyces cerevisiae

Modeling single-cell phenotypes links yeast stress acclimation to transcriptional repression and pre-stress cellular states

Dynamic trade-offs between biomass accumulation and division determine bacterial cell size and proteome in fluctuating nutrient environments

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