Recent functional insights into the role of (p)ppGpp in bacterial physiology

Hauryliuk, Vasili; Atkinson, Gemma C.; Murakami, Katsuhiko; Tenson, Tanel; Gerdes, Kenn

doi:10.1038/nrmicro3448

Cited by 711 publications

(799 citation statements)

References 130 publications

(206 reference statements)

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“…Specifically, transcriptomic and proteomic analysis demonstrated that E. faecalis strongly induces several high-affinity Fe, Mn, and Zn transporters in blood and urine, suggesting that acquisition of these trace elements is important for growth and persistence of E. faecalis in the host environment (19)(20)(21). To test if the growth and survival defects of the E. faecalis Δrel ΔrelQ [(p)ppGpp 0 ] strain in blood (or serum) are due to metal starvation, growth and survival of the parent (OG1RF) and (p)ppGpp 0 strains were monitored in plain horse serum (HS) or HS supplemented with 1 mM FeSO 4 , 1 mM MnSO 4 , or 1 mM ZnSO 4 . Zn is a transition metal essential for protein structure and function that is also withheld from pathogens during systemic infections and was therefore included in our panel of metal cofactors.…”

Section: Resultsmentioning

confidence: 99%

“…We also determined that the Zn concentration in all medium preparations was ϳ70 ng ml Ϫ1 . Considering that Zn is not a component of the FMC recipe, these small amounts of Zn were likely due to trace element contamination 4 . Aliquots taken at selected time points were serially diluted and plated on TSA plates for CFU enumeration.…”

Section: Resultsmentioning

confidence: 99%

“…In Firmicutes such as E. faecalis, (p)ppGpp controls transcription via two distinct mechanisms: (i) by changing the concentration of the initiating nucleotide of transcription (iNTP) (position ϩ1) and (ii) by modulating the DNA-binding capacity of CodY, a global metabolic regulator of nutrient transport, amino acid biosynthesis, and virulence (3,4,24). The ability of nutrient-sensing regulator CodY to bind to DNA and repress target gene expression is strongly enhanced in the presence of branched-chain amino acids (BCAA) and GTP (24).…”

Section: Resultsmentioning

confidence: 99%

“…During the SR, (p)ppGpp accumulation triggers transcriptional alterations that lead to general repression of rapid growth and simultaneous activation of stress survival, nutrient uptake, and biosynthesis pathways. In addition to its involvement in transcriptional control, (p)ppGpp allosterically inhibits the activity of several enzymes, including DNA primase, translation factors, and enzymes involved in GTP biosynthesis (3,4). Moreover, modest increases in (p)ppGpp levels, below those required to activate the SR, have been shown to contribute to restoration of cellular homeostasis under mildly stressful conditions (3).…”

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confidence: 99%

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Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

2017

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In Enterococcus faecalis, the regulatory nucleotides pppGpp and ppGpp, collectively, (p)ppGpp, are required for growth in blood, survival within macrophages, and virulence. However, a clear understanding of how (p)ppGpp promotes virulence in E. faecalis and other bacterial pathogens is still lacking. In the host, the essential transition metals iron (Fe) and manganese (Mn) are not readily available to invading pathogens because of a host-driven process called nutritional immunity. Considering its central role in adaptation to nutritional stresses, we hypothesized that (p)ppGpp mediates E. faecalis virulence through regulation of metal homeostasis. Indeed, supplementation of serum with either Fe or Mn restored growth and survival of the Δrel ΔrelQ [(p)ppGpp 0 ] strain to wild-type levels. Using a chemically defined medium, we found that (p)ppGpp accumulates in response to either Fe depletion or Mn depletion and that the (p)ppGpp 0 strain has a strong growth requirement for Mn that is alleviated by Fe supplementation. Although inactivation of the nutrient-sensing regulator codY restored some phenotypes of the (p)ppGpp 0 strain, transcriptional analysis showed that the (p)ppGpp/CodY network does not promote transcription of known metal transporters. Interestingly, physiologic and enzymatic investigations suggest that the (p)ppGpp 0 strain requires higher levels of Mn in order to cope with high levels of endogenously produced reactive oxygen species (ROS). Because (p)ppGpp mediates antibiotic persistence and virulence in several bacteria, our findings have broad implications and provide new leads for the development of novel therapeutic and preventive strategies against E. faecalis and beyond. KEYWORDS (p)ppGpp, Enterococcus, manganese, metal homeostasis, nutritional immunity, oxidative stress E nterococcus faecalis is a common member of the human gut microbiota but also a leading cause of a number of hospital-acquired infections such as endocarditis and surgical wound and urinary tract infections (1). The association of this opportunistic pathogen with disease relies on its exceptional resilience, which allows it to prevail in the unfavorable hospital setting while providing a competitive advantage over other bacteria during both infection and treatment.Among the most prominent regulators involved in bacterial adaptation to stress are the nucleotide second messengers guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), collectively, (p)ppGpp, best known as the effectors of the stringent response (SR) (2). While initially discovered to accumulate in response to amino acid starvation, (p)ppGpp has also been shown to accumulate in response to restrictions in carbon, fatty acids, and iron, as well as in response to other nonnutritional stresses (3). During the SR, (p)ppGpp accumulation triggers transcriptional alterations that lead to general repression of rapid growth and simultaneous activation of stress survival, nutrient uptake, and biosynthesis pathways. In addition to its involvement in...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

2017

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“…The specific nature of the starvation (i.e., the type of nutrient that has become limiting for growth) and the time spent under nutrient limiting conditions affect the accumulation of these modulators of transcription, presumably allowing cells to target their stress response to best compensate for the shortage of particular metabolites. 58,67-70 Similarly, we reckon that tRNA degradation may only be beneficial during exposure to a subset of the possible stressors a bacterium may encounter. In our study 14 (as in most other studies on the stringent response, reviewed in refs.…”

Section: Why Degrade Trna?mentioning

confidence: 99%

Transfer RNA instability as a stress response inEscherichia coli: Rapid dynamics of the tRNA pool as a function of demand

2018

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Production of the translation apparatus of E. coli is carefully matched to the demand for protein synthesis posed by a given growth condition. For example, the fraction of RNA polymerases that transcribe rRNA and tRNA drops from 80% during rapid growth to 24% within minutes of a sudden amino acid starvation. We recently reported in Nucleic Acids Research that the tRNA pool is more dynamically regulated than previously thought. In addition to the regulation at the level of synthesis, we found that tRNAs are subject to demand-based regulation at the level of their degradation. In this point-of-view article we address the question of why this phenomenon has not previously been described. We also present data that expands on the mechanism of tRNA degradation, and we discuss the possible implications of tRNA instability for the ability of E. coli to cope with stresses that affect the translation process.

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Phosphorylation of bacterial L9 and its functional implication in response to starvation stress

et al. 2017

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The bacterial L9 (bL9) protein expressed and purified from Escherichia coli is stably phosphorylated. We mapped seven Ser/Thr phosphorylation sites, all of which but one are located at the carboxyl-terminal domain (CTD). When a histidine tag is fused to the C-terminus, bL9 is no longer phosphorylated. Phosphorylation of bL9 causes complete disordering of its CTD and helps cell survival under nutrient-limiting conditions. Previous structural studies of the ribosome have shown that bL9 exhibits two distinct conformations, one of which competes with binding of RelA to the 30s rRNA and prevents RelA activation. Taken together, we suggest that the flexibility of the bL9 CTD enabled by phosphorylation would remove the steric hindrance, serving as a previously unknown mechanism to regulate RelA function and help cell survival under starvation stress.

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Recent functional insights into the role of (p)ppGpp in bacterial physiology

Cited by 711 publications

References 130 publications

Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis

Transfer RNA instability as a stress response inEscherichia coli: Rapid dynamics of the tRNA pool as a function of demand

Phosphorylation of bacterial L9 and its functional implication in response to starvation stress

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