A Conserved Switch Controls Virulence, Sporulation, and Motility in<i>C. difficile</i>

DiCandia, Michael A; Edwards, Adrianne N.; Lee, Cheyenne D; Monteiro, Marcos P; Vargas-Cuebas, Germán; Bagchi, Pritha; McBride, Shonna M.

doi:10.1101/2023.03.28.534590

Cited by 4 publications

(3 citation statements)

References 60 publications

(114 reference statements)

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“…The PtpA and PtpB regulatory pathway is linked with RstA, a multifunctional regulator that indirectly promotes sporulation and directly represses the expression of motility and toxin genes ( 58 , 59 , 69 , 70 ). RstA inhibits the function of Spo0E, a small protein that directly binds to Spo0A and prevents its activation ( 71 ). PtpA/B and RstA reciprocally regulate sporulation, toxin production, and motility, which suggests that the activities of the proteins converge on a shared regulatory pathway.…”

Section: Contribution Of Ohks To Sporulation Initiation By ...mentioning

confidence: 99%

The impact of orphan histidine kinases and phosphotransfer proteins on the regulation of clostridial sporulation initiation

Mehdizadeh Gohari,

Edwards,

McBride

et al. 2024

mBio

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Sporulation is an important feature of the clostridial life cycle, facilitating survival of these bacteria in harsh environments, contributing to disease transmission for pathogenic species, and sharing common early steps that are also involved in regulating industrially important solvent production by some non-pathogenic species. Initial genomics studies suggested that Clostridia lack the classical phosphorelay that phosphorylates Spo0A and initiates sporulation in Bacillus , leading to the hypothesis that sporulation in Clostridia universally begins when Spo0A is phosphorylated by orphan histidine kinases (OHKs). However, components of the classical Bacillus phosphorelay were recently identified in some Clostridia. Similar Bacillus phosphorelay components have not yet been found in the pathogenic Clostridia or the solventogenic Clostridia of industrial importance. For some of those Clostridia lacking a classical phosphorelay, the involvement of OHKs in sporulation initiation has received support from genetic studies demonstrating the involvement of several apparent OHKs in their sporulation. In addition, several clostridial OHKs directly phosphorylate Spo0A in vitro . Interestingly, there is considerable protein domain diversity among the sporulation-associated OHKs in Clostridia. Further adding to the emergent complexity of sporulation initiation in Clostridia, several candidate OHK phosphotransfer proteins that were OHK candidates were shown to function as phosphatases that reduce sporulation in some Clostridia. The mounting evidence indicates that no single pathway explains sporulation initiation in all Clostridia and supports the need for further study to fully understand the unexpected and biologically fascinating mechanistic diversity of this important process among these medically and industrially important bacteria.

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Section: Contribution Of Ohks To Sporulation Initiation By ...mentioning

confidence: 99%

The impact of orphan histidine kinases and phosphotransfer proteins on the regulation of clostridial sporulation initiation

Mehdizadeh Gohari,

Edwards,

McBride

et al. 2024

mBio

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“…The C . difficile RRNPP ortholog, RstA, positively influences spore formation by directly binding an inhibitor of sporulation [ 26 , 27 ]. However, RstA differs from most members of the RRNPP family in that its cognate quorum-sensing peptide is not adjacently encoded on the genome and has yet to be discovered [ 26 ], providing additional evidence that C .…”

Section: Introductionmentioning

confidence: 99%

“…directly bind small quorum-sensing peptides to regulate their activity, which impacts Spo0A phosphorylation [24,25]. The C. difficile RRNPP ortholog, RstA, positively influences spore formation by directly binding an inhibitor of sporulation [26,27]. However, RstA differs from most members of the RRNPP family in that its cognate quorum-sensing peptide is not adjacently encoded on the genome and has yet to be discovered [26], providing additional evidence that C. difficile employs distinct regulatory pathways to initiate sporulation.…”

Section: Introductionmentioning

confidence: 99%

The RgaS-RgaR two-component system promotes Clostridioides difficile sporulation through a small RNA and the Agr1 system

Edwards,

McBride

2023

PLoS Genet

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The ability to form a dormant spore is essential for the survival of the anaerobic pathogen, Clostridioides difficile, outside of the mammalian gastrointestinal tract. The initiation of sporulation is governed by the master regulator of sporulation, Spo0A, which is activated by phosphorylation. Multiple sporulation factors control Spo0A phosphorylation; however, this regulatory pathway is not well defined in C. difficile. We discovered that RgaS and RgaR, a conserved orphan histidine kinase and orphan response regulator, function together as a cognate two-component regulatory system to directly activate transcription of several genes. One of these targets, agrB1D1, encodes gene products that synthesize and export a small quorum-sensing peptide, AgrD1, which positively influences expression of early sporulation genes. Another target, a small regulatory RNA now known as SpoZ, impacts later stages of sporulation through a small hypothetical protein and an additional, unknown regulatory mechanism (s). Unlike Agr systems in many organisms, AgrD1 does not activate the RgaS-RgaR two-component system, and thus, is not responsible for autoregulating its own production. Altogether, we demonstrate that C. difficile utilizes a conserved two-component system that is uncoupled from quorum-sensing to promote sporulation through two distinct regulatory pathways.

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The RgaS-RgaR two-component system promotesClostridioides difficilesporulation through a small RNA and the Agr1 system

Edwards

McBride

2023

Preprint

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The ability to form a dormant spore is essential for the survival of the anaerobic, gastrointestinal pathogen Clostridioides difficile outside of the mammalian gastrointestinal tract. The initiation of sporulation is governed by the master regulator of sporulation, Spo0A, which is activated by phosphorylation. Multiple sporulation factors control Spo0A phosphorylation; however, this regulatory pathway is not well defined in C. difficile. We discovered that RgaS and RgaR, a conserved orphan histidine kinase and orphan response regulator, function together as a cognate two-component regulatory system to directly activate transcription of several genes. One of these targets, agrB1D1, encodes gene products that synthesize and export a small quorum-sensing peptide, AgrD1, which positively influences expression of early sporulation genes. Another target, a small regulatory RNA now known as SrsR, impacts later stages of sporulation through an unknown regulatory mechanism(s). Unlike Agr systems in many organisms, AgrD1 does not activate the RgaS-RgaR two-component system, and thus, is not responsible for autoregulating its own production. Altogether, we demonstrate that C. difficile utilizes a conserved two-component system that is uncoupled from quorum-sensing to promote sporulation through two distinct regulatory pathways.

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A Conserved Switch Controls Virulence, Sporulation, and Motility inC. difficile

Cited by 4 publications

References 60 publications

The impact of orphan histidine kinases and phosphotransfer proteins on the regulation of clostridial sporulation initiation

The impact of orphan histidine kinases and phosphotransfer proteins on the regulation of clostridial sporulation initiation

The RgaS-RgaR two-component system promotes Clostridioides difficile sporulation through a small RNA and the Agr1 system

The RgaS-RgaR two-component system promotesClostridioides difficilesporulation through a small RNA and the Agr1 system

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