Complexity in bacterial cell–cell communication: Quorum signal integration and subpopulation signaling in the
            <i>Bacillus subtilis</i>
            phosphorelay

Bischofs, Ilka B.; Hug, Joshua Adam; Liu, Aiwen W.; Wolf, Denise M.; Arkin, Adam P.

doi:10.1073/pnas.0810878106

Cited by 93 publications

(107 citation statements)

References 33 publications

(52 reference statements)

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“…This is currently under investigation in our laboratory. Interestingly, the subpopulation of nonsporulating cells demonstrated an interesting pulsating gene expression pattern during microcolony development, which resembles recently reported fluctuations of rapA and sda gene expression (3,48). It is tempting to speculate that cells undergo cell cycle-dependent regulation of the activity of Spo0AϳP as a "bet-hedging" strategy to ensure that cells will sporulate only when the conditions are favorable again to bifurcate into sporulating and nonsporulating populations (50).…”

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confidence: 84%

Heterochronic Phosphorelay Gene Expression as a Source of Heterogeneity in Bacillus subtilis Spore Formation

2010

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In response to limiting nutrient sources and cell density signals, Bacillus subtilis can differentiate and form highly resistant endospores. Initiation of spore development is governed by the master regulator Spo0A, which is activated by phosphorylation via a multicomponent phosphorelay. Interestingly, only part of a clonal population will enter this developmental pathway, a phenomenon known as sporulation bistability or sporulation heterogeneity. How sporulation heterogeneity is established is largely unknown. To investigate the origins of sporulation heterogeneity, we constructed promoter-green fluorescent protein (GFP) fusions to the main phosphorelay genes and perturbed their expression levels. Using time-lapse fluorescence microscopy and flow cytometry, we showed that expression of the phosphorelay genes is distributed in a unimodal manner. However, single-cell trajectories revealed that phosphorelay gene expression is highly dynamic or "heterochronic" between individual cells and that stochasticity of phosphorelay gene transcription might be an important regulatory mechanism for sporulation heterogeneity. Furthermore, we showed that artificial induction or depletion of the phosphorelay phosphate flow results in loss of sporulation heterogeneity. Our data suggest that sporulation heterogeneity originates from highly dynamic and variable gene activity of the phosphorelay components, resulting in large cell-to-cell variability with regard to phosphate input into the system. These transcriptional and posttranslational differences in phosphorelay activity appear to be sufficient to generate a heterogeneous sporulation signal without the need of the positive-feedback loop established by the sigma factor SigH.When nutrient sources are dwindling, the Gram-positive bacterium Bacillus subtilis can utilize a number of adaptive phenotypes such as the secretion of proteases and the development of genetic competence (for a recent review, see reference 49). The most sophisticated survival strategy that B. subtilis employs is the formation of a highly resistant endospore (34). Initiation of spore formation is governed by a complex multicomponent phosphorelay (Fig. 1) including the primary kinases KinA and KinB and two intermediate phosphotransferases, Spo0B and Spo0F (33). The phosphorelay activates Spo0A, the master sporulation regulator of sporulation, by phosphorylation (4), upon which phosphorylated Spo0A (Spo0AϳP) can directly regulate more than 100 genes (29). This induces a chain of events that takes several hours to complete and involves the activation of a set of alternative sigma factors that give unidirectionality to the cascade, culminating in the formation of the endospore (10).Interestingly, within isogenic populations of B. subtilis grown under identical conditions, not all cells enter this timely and costly developmental pathway. This type of phenotypic bifurcation is known as sporulation bistability or sporulation heterogeneity (9, 38). How populations of genetically identical cells bifurcate into phenoty...

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confidence: 84%

Heterochronic Phosphorelay Gene Expression as a Source of Heterogeneity in Bacillus subtilis Spore Formation

2010

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“…Several previous studies have hypothesized that sporulation is triggered in cells reaching a threshold level of Spo0A∼P (14)(15)(16)(17)(18). This hypothesis is motivated by the observation that an increase in Spo0A∼P is sufficient to shift the site of cell division to an asymmetrical polar site, and thereby to initiate sporulation (19,20).…”

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confidence: 99%

Ultrasensitivity of the Bacillus subtilis sporulation decision

Narula

Devi

Fujita

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Starving Bacillus subtilis cells execute a gene expression program resulting in the formation of stress-resistant spores. Sporulation master regulator, Spo0A, is activated by a phosphorelay and controls the expression of a multitude of genes, including the forespore-specific sigma factor σ F and the mother cell-specific sigma factor σ E . Identification of the system-level mechanism of the sporulation decision is hindered by a lack of direct control over Spo0A activity. This limitation can be overcome by using a synthetic system in which Spo0A activation is controlled by inducing expression of phosphorelay kinase KinA. This induction results in a switch-like increase in the number of sporulating cells at a threshold of KinA. Using a combination of mathematical modeling and single-cell microscopy, we investigate the origin and physiological significance of this ultrasensitive threshold. The results indicate that the phosphorelay is unable to achieve a sufficiently fast and ultrasensitive response via its positive feedback architecture, suggesting that the sporulation decision is made downstream. In contrast, activation of σ F in the forespore and of σ E in the mother cell compartments occurs via a cascade of coherent feed-forward loops, and thereby can produce fast and ultrasensitive responses as a result of KinA induction. Unlike σ F activation, σ E activation in the mother cell compartment only occurs above the KinA threshold, resulting in completion of sporulation. Thus, ultrasensitive σ E activation explains the KinA threshold for sporulation induction. We therefore infer that under uncertain conditions, cells initiate sporulation but postpone making the sporulation decision to average stochastic fluctuations and to achieve a robust population response.cell fate | development | differentiation | stochasticity | network I n response to nutrient deprivation, Bacillus subtilis cells undergo asymmetrical cell division and then follow a cell differentiation program resulting in formation of metabolically inert spores (1, 2) (Fig. 1A). Sporulation requires the execution of a complex gene expression program involving hundreds of "sporulation" genes (3-6). The availability of a large number of genetic mutants that differ from the WT only in their sporulation response makes B. subtilis an ideal model system to study the relationship between gene expression and cell fate specification during bacterial differentiation (7).Progression of the sporulation program is under the control of a large regulatory network (hereafter called the sporulation network). This network involves the sporulation master regulator Spo0A and five alternative sigma factors (σ H , σ F , σ E , σ K , and σ G ) that are activated in precise temporal order (8). Initiation of the sporulation program is controlled by Spo0A (4, 9). The activity and concentration of this master transcription factor are regulated by phosphorelay through both posttranslational and transcriptional interactions (10). Posttranslationally, phosphoryl groups are transferred fro...

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“…Other modeling studies of the phosphorelay cascades of kinases by Huang and Ferrell (17) show that a cooperative-like behavior can be obtained without the hallmarks of molecular cooperativity under equilibrium conditions. Modeling of protein-antagonist motifs such as the Sin or the Rap modules by Arkin and collaborators (18,19) has demonstrated how the dynamical modes of these circuits depend on the physiological parameters.…”

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confidence: 99%

Deciding fate in adverse times: Sporulation and competence in Bacillus subtilis

Schultz

Wolynes

Jacob

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

181

192

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Bacteria serve as the central arena for understanding how gene networks and proteins process information and control cellular behaviors. Recently, much effort has been devoted to the investigation of specific bacteria gene circuits as functioning modules. The next challenge is the integrative modeling of complex cellular networks composed of many such modules. A tractable integrative model of the sophisticated decision-making signal transduction system that determines the fate between sporulation and competence is presented. This model provides an understanding of how information is sensed and processed to reach an ''informative'' decision in the context of cell state and signals from other cells. The competence module (ComK dynamics) is modeled as a stochastic switch whose transition rate is controlled by a quorum-sensing unit. The sporulation module (Spo0A dynamics) is modeled as a timer whose clock rate is adjusted by a stress-sensing unit. The interplay between these modules is mediated via the Rap assessment system, which gates the sensing units, and the AbrB-Rok decision module, which creates an opportunity for competence within a specific window of the sporulation timer. The timer is regulated via a special repressilator-like inhibition of Spo0A* by Spo0E, which is itself inhibited by AbrB. For some stress and input signals, this repressilator can generate a frustration state with large variations (fluctuations or oscillations) in Spo0A* and AbrB concentrations, which might serve an important role in generating cell variability. This integrative framework is a starting point that can be extended to include transition into cannibalism and the role of colony organization.

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Complexity in bacterial cell–cell communication: Quorum signal integration and subpopulation signaling in the Bacillus subtilis phosphorelay

Cited by 93 publications

References 33 publications

Heterochronic Phosphorelay Gene Expression as a Source of Heterogeneity in Bacillus subtilis Spore Formation

Heterochronic Phosphorelay Gene Expression as a Source of Heterogeneity in Bacillus subtilis Spore Formation

Ultrasensitivity of the Bacillus subtilis sporulation decision

Deciding fate in adverse times: Sporulation and competence in Bacillus subtilis

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