Bacillus subtilis extracytoplasmic function (ECF) sigma factors and defense of the cell envelope

Helmann, John D.

doi:10.1016/j.mib.2016.02.002

Cited by 116 publications

(177 citation statements)

References 94 publications

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“…This is consistent with the morphological changes induced by other genetic and chemical perturbations known to affect peptidoglycan synthesis. Concomitant with the onset of morphological defects resulting from depletion of UPP, the cells strongly activate the M cell envelope stress response, consistent with the effects of other antibiotics that target the lipid II cycle (53).…”

Section: Discussionsupporting

confidence: 67%

“…A common feature of many different compounds that inhibit the lipid II cycle is that they invoke cell envelope stress responses, including activation of the M regulon (53). A major function of the M regulon is to increase the expression of key enzymes involved in cell envelope synthesis and to upregulate alternative enzymes to replace those that might be inhibited.…”

Section: Discussionmentioning

confidence: 99%

“…Notable examples of M -dependent compensation reactions include upregulation of the lipid II flippase Amj (which substitutes for MurJ) (5), the lipoteichoic acid synthase LtaSa (YfnI, which substitutes for LtaS), and BcrC (which substitutes for UppP) (19,50). Similarly, antibiotics that inhibit the lipid II cycle, including bacitracin (48), vancomycin (50), moenomycin (54), and the WTA-targeting targocil (46), all activate the M regulon (53). In the work presented here, we set out to explore the role of three genes encoding candidate UPP-Pases in the lipid II cycle in B. subtilis.…”

Section: Discussionmentioning

confidence: 99%

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Depletion of Undecaprenyl Pyrophosphate Phosphatases Disrupts Cell Envelope Biogenesis in Bacillus subtilis

et al. 2016

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The integrity of the bacterial cell envelope is essential to sustain life by countering the high turgor pressure of the cell and providing a barrier against chemical insults. In Bacillus subtilis, synthesis of both peptidoglycan and wall teichoic acids requires a common C 55 lipid carrier, undecaprenyl-pyrophosphate (UPP), to ferry precursors across the cytoplasmic membrane. The synthesis and recycling of UPP requires a phosphatase to generate the monophosphate form Und-P, which is the substrate for peptidoglycan and wall teichoic acid synthases. Using an optimized clustered regularly interspaced short palindromic repeat (CRISPR) system with catalytically inactive ("dead") CRISPR-associated protein 9 (dCas9)-based transcriptional repression system (CRISPR interference [CRISPRi]), we demonstrate that B. subtilis requires either of two UPP phosphatases, UppP or BcrC, for viability. We show that a third predicted lipid phosphatase (YodM), with homology to diacylglycerol pyrophosphatases, can also support growth when overexpressed. Depletion of UPP phosphatase activity leads to morphological defects consistent with a failure of cell envelope synthesis and strongly activates the M -dependent cell envelope stress response, including bcrC, which encodes one of the two UPP phosphatases. These results highlight the utility of an optimized CRISPRi system for the investigation of synthetic lethal gene pairs, clarify the nature of the B. subtilis UPP-Pase enzymes, and provide further evidence linking the M regulon to cell envelope homeostasis pathways. IMPORTANCEThe emergence of antibiotic resistance among bacterial pathogens is of critical concern and motivates efforts to develop new therapeutics and increase the utility of those already in use. The lipid II cycle is one of the most frequently targeted processes for antibiotics and has been intensively studied. Despite these efforts, some steps have remained poorly defined, partly due to genetic redundancy. CRISPRi provides a powerful tool to investigate the functions of essential genes and sets of genes. Here, we used an optimized CRISPRi system to demonstrate functional redundancy of two UPP phosphatases that are required for the conversion of the initially synthesized UPP lipid carrier to Und-P, the substrate for the synthesis of the initial lipid-linked precursors in peptidoglycan and wall teichoic acid synthesis.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Depletion of Undecaprenyl Pyrophosphate Phosphatases Disrupts Cell Envelope Biogenesis in Bacillus subtilis

et al. 2016

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“…Three major functions are linked to this situation: overcoming deleterious actions of non‐living and living organisms, escaping to other niches, possibly far away or staying in place. Bacillus subtilis monitors this situation via specific sigma factors (Helmann, 2016) and protein phosphorylation cascades (Schultz, 2016; Pane‐Farre et al ., 2017). These will not be further discussed here (except to note that the concept of stress being very ambiguous, as all living organisms suffer multiple transitions, it should probably be avoided to be replaced by the idea of transition management).…”

Section: Bacillus Subtilis Exploring Its Environmentmentioning

confidence: 99%

Bacillus subtilis, the model Gram‐positive bacterium: 20 years of annotation refinement

Borriss

Danchin

Harwood

et al. 2017

Microbial Biotechnology

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SummaryGenome annotation is, nowadays, performed via automatic pipelines that cannot discriminate between right and wrong annotations. Given their importance in increasing the accuracy of the genome annotations of other organisms, it is critical that the annotations of model organisms reflect the current annotation gold standard. The genome of Bacillus subtilis strain 168 was sequenced twenty years ago. Using a combination of inductive, deductive and abductive reasoning, we present a unique, manually curated annotation, essentially based on experimental data. This reveals how this bacterium lives in a plant niche, while carrying a paleome operating system common to Firmicutes and Tenericutes. Dozens of new genomic objects and an extensive literature survey have been included for the sequence available at the INSDC (AccNum AL009126.3). We also propose an extension to Demerec's nomenclature rules that will help investigators connect to this type of curated annotation via the use of common gene names.

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“…1, green). This is due to the fact that the regulons controlled by the major ECFs involved in CESR-σ M , σ W , and σ X -are rather complex (Helmann 2016): σ M controls the largest regulon of about 60 genes, many of which are key for cell envelope homeostasis (Eiamphungporn and Helmann 2008). σ W controls an 'antibiosis regulon' that also consists of about 60 genes, with many of the functions related to antibiotic resistance, especially against membrane-active agents.…”

Section: The Static Picture: Signaling Devices and Inducer Spectramentioning

confidence: 99%

The cell envelope stress response of Bacillus subtilis: from static signaling devices to dynamic regulatory network

2016

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The cell envelope stress response (CESR) encompasses all regulatory events that enable a cell to protect the integrity of its envelope, an essential structure of any bacterial cell. The underlying signaling network is particularly well understood in the Gram-positive model organism Bacillus subtilis. It consists of a number of two-component systems (2CS) and extracytoplasmic function σ factors that together regulate the production of both specific resistance determinants and general mechanisms to protect the envelope against antimicrobial peptides targeting the biogenesis of the cell wall. Here, we summarize the current picture of the B. subtilis CESR network, from the initial identification of the corresponding signaling devices to unraveling their interdependence and the underlying regulatory hierarchy within the network. In the course of detailed mechanistic studies, a number of novel signaling features could be described for the 2CSs involved in mediating CESR. This includes a novel class of so-called intramembrane-sensing histidine kinases (IM-HKs), which-instead of acting as stress sensors themselves-are activated via interprotein signal transfer. Some of these IM-HKs are involved in sensing the flux of antibiotic resistance transporters, a unique mechanism of responding to extracellular antibiotic challenge.

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Bacillus subtilis extracytoplasmic function (ECF) sigma factors and defense of the cell envelope

Cited by 116 publications

References 94 publications

Depletion of Undecaprenyl Pyrophosphate Phosphatases Disrupts Cell Envelope Biogenesis in Bacillus subtilis

Depletion of Undecaprenyl Pyrophosphate Phosphatases Disrupts Cell Envelope Biogenesis in Bacillus subtilis

Bacillus subtilis, the model Gram‐positive bacterium: 20 years of annotation refinement

The cell envelope stress response of Bacillus subtilis: from static signaling devices to dynamic regulatory network

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