Similar and Divergent Roles of Stringent Regulator (p)ppGpp and DksA on Pleiotropic Phenotype of Yersinia enterocolitica

Huang, Can; Meng, Jiao; Li, Wenqian; Chen, Jing Yu

doi:10.1128/spectrum.02055-22

Cited by 7 publications

(22 citation statements)

References 50 publications

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“…Previous reports have shown that (p)ppGpp and DksA have extensive regulatory roles in Escherichia coli and Xanthomonas citri [9,10]. Our previous studies on Y. enterocolitica also showed that the regulatory patterns of (p)ppGpp and DksA at the phenotypic and genotypic levels are complex, showing both synergistic and antagonistic actions [27]. To better understand the function of (p)ppGpp and DksA in cellular processes in Y. enterocolitica, RNA-Seq was conducted to determine the transcription profiles of wild-type and mutant strains, including Y. enterocolitica ∆dksA, Y. enterocolitica ∆relA∆spoT, and Y. enterocolitica ∆dksA∆relA∆spoT.…”

Section: (P)ppgpp-and Dksa-dependent Genes In Y Enterocolitica Identi...mentioning

confidence: 69%

“…Although studies have confirmed that DksA is the main cofactor of (p)ppGpp during stringent response, (p)ppGpp-and DksA-deficient strains display differences at the genotypic and phenotypic levels [25,37]. Our previous studies also showed that DksA and (p)ppGpp cooperatively regulate antibiotic resistance and environmental tolerance in Y. enterocolitica, whereas they exhibit dependent or independent roles in biofilm synthesis [27]. To comprehensively understand the regulatory function of the stringent response in Y. enterocolitica, WT and the mutant strains ∆dksA, ∆relA∆spoT, and ∆dksA∆relA∆spoT were subjected to comparative transcriptome analysis and phenotypic characterization.…”

Section: Discussionmentioning

confidence: 80%

“…Among these genes, only flhD was significantly upregulated (FC > 2), whereas the remaining genes (fliN, flgI, flgH, flgE, flgD, fliQ, fliS, fliT, flgG, flgF, fliJ, fliK, fliR, and fliC) were significantly downregulated (FC < 2). The decreased expression of these flagellar genes may be responsible for the decreased motility and flagellar formation ability of ∆relA∆spoT [27]. In addition, the expression levels of these genes in ∆dksA∆relA∆spoT were more similar to those in ∆dksA than in ∆relA∆spoT, indicating that DksA plays a more critical role in the regulation of flagellar biosynthesis during stringent response.…”

Section: Dksa and Ppgpp Positively Affect Bacterial Chemotaxismentioning

confidence: 95%

“…We recently characterized a part of the physiological activity regulated by the stringent response factors (p)ppGpp and DksA in Y. enterocolitica [27]. It was found that (p)ppGpp and DksA synergistically regulate the motility, antibiotic resistance, and tolerance to oxidative stress of Y. enterocolitica but have independent or opposite effects on bacterial biofilm formation and tolerance to acid and a hyperosmotic environment.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic Analysis Reveals Key Roles of (p)ppGpp and DksA in Regulating Metabolism and Chemotaxis in Yersinia enterocolitica

Huang

Chen

2023

IJMS

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The stringent response is a rapid response system that is ubiquitous in bacteria, allowing them to sense changes in the external environment and undergo extensive physiological transformations. However, the regulators (p)ppGpp and DksA have extensive and complex regulatory patterns. Our previous studies demonstrated that (p)ppGpp and DksA in Yersinia enterocolitica positively co-regulated motility, antibiotic resistance, and environmental tolerance but had opposite roles in biofilm formation. To reveal the cellular functions regulated by (p)ppGpp and DksA comprehensively, the gene expression profiles of wild-type, ΔrelA, ΔrelAΔspoT, and ΔdksAΔrelAΔspoT strains were compared using RNA-Seq. Results showed that (p)ppGpp and DksA repressed the expression of ribosomal synthesis genes and enhanced the expression of genes involved in intracellular energy and material metabolism, amino acid transport and synthesis, flagella formation, and the phosphate transfer system. Additionally, (p)ppGpp and DksA inhibited amino acid utilization (such as arginine and cystine) and chemotaxis in Y. enterocolitica. Overall, the results of this study unraveled the link between (p)ppGpp and DksA in the metabolic networks, amino acid utilization, and chemotaxis in Y. enterocolitica and enhanced the understanding of stringent responses in Enterobacteriaceae.

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Section: (P)ppgpp-and Dksa-dependent Genes In Y Enterocolitica Identi...mentioning

confidence: 69%

Section: Discussionmentioning

confidence: 80%

Section: Dksa and Ppgpp Positively Affect Bacterial Chemotaxismentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Transcriptomic Analysis Reveals Key Roles of (p)ppGpp and DksA in Regulating Metabolism and Chemotaxis in Yersinia enterocolitica

Huang

Chen

2023

IJMS

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“…The (p)ppGpp alone or in combination with DksA interacts with RNAP to regulate transcriptional responses of more than 750 genes in E. coli (15,16). The role of (p)ppGpp and DksA in modulating the antimicrobial susceptibility has been studied in different pathogens (17)(18)(19)(20)(21)(22), however, the mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

(p)ppGpp and DksA play crucial role in reducing the efficacy of β-lactam antibiotics by modulating bacterial membrane permeability

Chawla,

Verma,

Kumari

et al. 2024

Preprint

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The key signaling molecules in the bacterial stress sensing pathway, the alarmone (p)ppGpp and transcription factor DksA, help in survival during nutritional deprivation and exposure to xenobiotics by modulating cellular metabolic pathways. In Vibrio cholerae, (p)ppGpp metabolism is solely linked with the functions of three proteins: RelA, SpoT, and RelV. At threshold or elevated concentrations of (p)ppGpp, the level of cellular metabolites and proteins in the presence and absence of DksA in V. cholerae and other bacteria has not yet been comprehensively studied. We engineered the genome of V. cholerae to develop DksA null mutants in the presence and absence of (p)ppGpp biosynthetic enzymes. We observed a higher sensitivity of the (p)ppGpp0ΔdksA V. cholerae mutant to different β-lactam antibiotics compared to the wild-type (WT) strain. Our whole-cell metabolomic and proteome analysis revealed that the cell membrane and peptidoglycan biosynthesis pathways are significantly altered in the (p)ppGpp0, ΔdksA, and (p)ppGpp0ΔdksA V. cholerae strains. Further, the mutant strains displayed enhanced inner and outer membrane permeability in comparison to the WT strains. These results directly correlate with the tolerance and survival of V. cholerae to β-lactam antibiotics. These findings may help in the development of adjuvants for β-lactam antibiotics by inhibiting the functions of stringent response modulators.

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The transcription factor DksA exerts opposing effects on cell division depending on the presence of ppGpp

Anderson

Vadia

McKelvy

et al. 2023

Preprint

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Bacterial cell size is a multifactorial trait that is influenced by variables including nutritional availability and the timing of cell division. Prior work revealed a negative correlation between the alarmone (p)ppGpp (ppGpp) and cell length inEscherichia coli, suggesting that ppGpp may promote assembly of the division machinery (divisome) and cytokinesis in this organism. To clarify this counterintuitive connection between a starvation induced stress response effector and cell proliferation, we undertook a systematic analysis of growth and division inE. colicells defective in ppGpp synthesis and/or engineered to overproduce the alarmone. Our data indicate that ppGpp acts indirectly on divisome assembly through its role as a global mediator of transcription. Loss of either ppGpp (ppGpp0) or the ppGpp-associated transcription factor DksA led to increased average length, with ppGpp0mutants also exhibiting a high frequency of extremely long filamentous cells. Using heat-sensitive division mutants and fluorescently labeled division proteins, we confirmed that ppGpp and DksA are cell division activators. We found that ppGpp and DksA regulate division through their effects on transcription, although the lack of known division genes or regulators in available transcriptomics data strongly suggests that this regulation is indirect. Surprisingly, we also found that DksA inhibits division in ppGpp0cells, contrary to its role in a wild-type background. We propose that the ability of ppGpp to switch DksA from a division inhibitor to a division activator helps tune cell length across different concentrations of ppGpp.ImportanceCell division is a key step in the bacterial lifecycle that must be appropriately regulated to ensure survival. This work identifies the alarmone ppGpp as a general regulator of cell division, extending our understanding of the role of ppGpp beyond a signal for starvation and other stress. Even in nutrient replete conditions, basal levels of ppGpp are essential for division to occur appropriately and for cell size to be maintained. This study establishes ppGpp as a “switch” that controls whether the transcription factor DksA behaves as a division activator or inhibitor. This unexpected finding enhances our understanding of the complex regulatory mechanisms employed by bacteria to coordinate division with diverse aspects of cell growth and stress response. Because division is an essential process, a better understanding the mechanisms governing assembly and activation of the division machinery could contribute to the development of novel therapeutics to treat bacterial infections.

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Similar and Divergent Roles of Stringent Regulator (p)ppGpp and DksA on Pleiotropic Phenotype of Yersinia enterocolitica

Abstract: The synergetic actions between the stringent response signaling molecules, (p)ppGpp and DksA, have been widely reported. However, recent transcriptomic and phenotypic studies have suggested that independent or even opposite actions exist between them.

Cited by 7 publications

References 50 publications

Transcriptomic Analysis Reveals Key Roles of (p)ppGpp and DksA in Regulating Metabolism and Chemotaxis in Yersinia enterocolitica

Transcriptomic Analysis Reveals Key Roles of (p)ppGpp and DksA in Regulating Metabolism and Chemotaxis in Yersinia enterocolitica

(p)ppGpp and DksA play crucial role in reducing the efficacy of β-lactam antibiotics by modulating bacterial membrane permeability

The transcription factor DksA exerts opposing effects on cell division depending on the presence of ppGpp

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