<scp>ComGA</scp>‐<scp>RelA</scp> interaction and persistence in the <scp><i>B</i></scp><i>acillus subtilis</i> <scp>K</scp>‐state

Hahn, Jeanette; Tanner, Andrew W.; Carabetta, Valerie J.; Cristea, Ileana M.; Dubnau, David

doi:10.1111/mmi.13040

Cited by 52 publications

(48 citation statements)

References 86 publications

(132 reference statements)

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“…The K-state appears to be a persistent state in which a trade off between the costs of growth-arrest and the expression of the competence machinery are balanced by fitness benefits due to tolerance in the face of environmental insults, e.g., exposure to antibiotics (Nester and Stocker, 1963; Johnsen et al, 2009; Hahn et al, 2015; Yuksel et al, 2016), as well as the ability to acquire useful genetic information. In the face of this trade-off, bet-hedging due to the bistable expression of the K-state, presumably helps to maximize fitness (Dubnau and Losick, 2006; Veening et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Because these genes are not needed for transformation (J. Hahn, unpublished) the expression of ComK must result in phenotypes beyond competence that presumably enhance fitness. In fact, ComK also induces a period of growth arrest during which the cells that express ComK exhibit antibiotic tolerance (Nester and Stocker, 1963; Haijema et al, 2001; Johnsen et al, 2009; Briley et al, 2011; Hahn et al, 2015; Yuksel et al, 2016). This persistent state has been called the K-state, to emphasize that ComK regulates more than competence for transformation (Berka et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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A DegU-P and DegQ-Dependent Regulatory Pathway for the K-state in Bacillus subtilis

Miras

Dubnau

2016

Front. Microbiol.

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The K-state in the model bacterium Bacillus subtilis is associated with transformability (competence) as well as with growth arrest and tolerance for antibiotics. Entry into the K-state is determined by the stochastic activation of the transcription factor ComK and occurs in about ∼15% of the population in domesticated strains. Although the upstream mechanisms that regulate the K-state have been intensively studied and are well understood, it has remained unexplained why undomesticated isolates of B. subtilis are poorly transformable compared to their domesticated counterparts. We show here that this is because fewer cells enter the K-state, suggesting that a regulatory pathway limiting entry to the K-state is missing in domesticated strains. We find that loss of this limitation is largely due to an inactivating point mutation in the promoter of degQ. The resulting low level of DegQ decreases the concentration of phosphorylated DegU, which leads to the de-repression of the srfA operon and ultimately to the stabilization of ComK. As a result, more cells reach the threshold concentration of ComK needed to activate the auto-regulatory loop at the comK promoter. In addition, we demonstrate that the activation of srfA transcription in undomesticated strains is transient, turning off abruptly as cells enter the stationary phase. Thus, the K-state and transformability are more transient and less frequently expressed in the undomesticated strains. This limitation is more extreme than appreciated from studies of domesticated strains. Selection has apparently limited both the frequency and the duration of the bistably expressed K-state in wild strains, likely because of the high cost of growth arrest associated with the K-state. Future modeling of K-state regulation and of the fitness advantages and costs of the K-state must take these features into account.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A DegU-P and DegQ-Dependent Regulatory Pathway for the K-state in Bacillus subtilis

Miras

Dubnau

2016

Front. Microbiol.

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“…Among the proteins encoded by these genes are those that enable the uptake and processing of transforming DNA; K-state cells are thus genetically competent for transformation. In addition, K-state cells are arrested for growth and division and are tolerant of a number of antibiotics (Hahn et al, 2015). Importantly, the K-state is bistably expressed, turning on in a subpopulation of cells.…”

Section: Introductionmentioning

confidence: 99%

Viscous drag on the flagellum activates Bacillus subtilis entry into the K‐state

Diethmaier

Chawla

Canzoneri

et al. 2017

Molecular Microbiology

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Bacillus subtilis flagella are not only required for locomotion but also act as sensors that monitor environmental changes. Although how the signal transmission takes place is poorly understood, it has been shown that flagella play an important role in surface sensing by transmitting a mechanical signal to control the DegS-DegU two-component system. Here we report a role for flagella in the regulation of the K-state, which enables transformability and antibiotic tolerance (persistence). Mutations impairing flagellar synthesis are inferred to increase DegU-P, which inhibits the expression of ComK, the master regulator for the K-state, and reduces transformability. Tellingly, both deletion of the flagellin gene and straight filament (hagA233V) mutations increased DegU phosphorylation despite the fact that both mutants had wild type numbers of basal bodies and the flagellar motors were functional. We propose that higher viscous loads on flagellar motors result in lower DegU-P levels through an unknown signaling mechanism. This flagellar-load based mechanism ensures that cells in the motile subpopulation have a 10-fold enhanced likelihood of entering the K-state and taking up DNA from the environment. Further, our results suggest that the developmental states of motility and competence are related and most commonly occur in the same epigenetic cell type.

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“…New microscopy approaches are emerging to better comprehend the mechanisms involved in the process of transformation. In recent times, several studies revealed the formation of tDNA foci on the surface of competent bacteria (Stingl et al, 2010;Berge et al, 2013;Gangel et al, 2014;Hahn et al, 2015;Kruger et al, 2016). Only one group followed by microscopy the tDNA passage into the cytoplasm .…”

Section: Introductionmentioning

confidence: 99%

Following transforming DNA in Helicobacter pylori from uptake to expression

Corbinais

Mathieu

Kortulewski

et al. 2016

Molecular Microbiology

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Natural transformation is a potent driver for genetic diversification in bacterial populations. It involves exogenous DNA binding, uptake, transport and internalization into the cytoplasm, where DNA can be processed and integrated into the host chromosome. Direct visualisation of transforming DNA (tDNA) has been limited to its binding to the surface or, in the case of Gram-negative species, to its entrance into the periplasm. We present here for the first time the direct visualisation of tDNA entering the bacterial cytoplasm. We used as a model the Gram-negative pathogen Helicobacter pylori, characterised by a large intraspecies variability that results from high mutation rates and efficient horizontal gene transfer. Using fluorescently labelled DNA, we followed for up to 3 h the fate of tDNA foci formed in the periplasm and eventually internalised into the cytoplasm. By tracking at the single cell level the expression of a fluorescent protein coded by the tDNA, we show that up to 50% of the cells express the transforming phenotype. The overall transformation process in H. pylori, from tDNA uptake to expression of the recombinant gene, can take place in less than 1 h, without requiring a growth arrest, and prior to the replication of the chromosome.

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ComGA‐RelA interaction and persistence in the Bacillus subtilis K‐state

Cited by 52 publications

References 86 publications

A DegU-P and DegQ-Dependent Regulatory Pathway for the K-state in Bacillus subtilis

A DegU-P and DegQ-Dependent Regulatory Pathway for the K-state in Bacillus subtilis

Viscous drag on the flagellum activates Bacillus subtilis entry into the K‐state

Following transforming DNA in Helicobacter pylori from uptake to expression

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