Polyphosphate is an extracellular signal that can facilitate bacterial survival in eukaryotic cells

Rijal, Ramesh; Cadena, Louis A.; Smith, Morgan; Carr, Joseph F; Gomer, Richard H.

doi:10.1073/pnas.2012009117

Cited by 38 publications

(50 citation statements)

References 91 publications

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“…PolyP also serves as a nucleation source for amyloid proteins ranging from human α-synuclein and Tau to the E. coli biofilm protein CsgA [ 1 , 29 ]. Finally, several recent studies have demonstrated that bacterial polyP can modulate the mammalian immune response [ 30 , 31 ], suggesting an intriguing potential for host–pathogen polyP crosstalk during infection [ 32 ].…”

Section: Introduction: Inorganic Polyphosphate and Polyphosphate Kinase 1 (Ppk1)mentioning

confidence: 99%

Polyphosphate Kinase 2 (PPK2) Enzymes: Structure, Function, and Roles in Bacterial Physiology and Virulence

Neville

Roberge

Jia

2022

IJMS

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Inorganic polyphosphate (polyP) has been implicated in an astonishing array of biological functions, ranging from phosphorus storage to molecular chaperone activity to bacterial virulence. In bacteria, polyP is synthesized by polyphosphate kinase (PPK) enzymes, which are broadly subdivided into two families: PPK1 and PPK2. While both enzyme families are capable of catalyzing polyP synthesis, PPK1s preferentially synthesize polyP from nucleoside triphosphates, and PPK2s preferentially consume polyP to phosphorylate nucleoside mono- or diphosphates. Importantly, many pathogenic bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii encode at least one of each PPK1 and PPK2, suggesting these enzymes may be attractive targets for antibacterial drugs. Although the majority of bacterial polyP studies to date have focused on PPK1s, PPK2 enzymes have also begun to emerge as important regulators of bacterial physiology and downstream virulence. In this review, we specifically examine the contributions of PPK2s to bacterial polyP homeostasis. Beginning with a survey of the structures and functions of biochemically characterized PPK2s, we summarize the roles of PPK2s in the bacterial cell, with a particular emphasis on virulence phenotypes. Furthermore, we outline recent progress on developing drugs that inhibit PPK2 enzymes and discuss this strategy as a novel means of combatting bacterial infections.

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Section: Introduction: Inorganic Polyphosphate and Polyphosphate Kinase 1 (Ppk1)mentioning

confidence: 99%

Polyphosphate Kinase 2 (PPK2) Enzymes: Structure, Function, and Roles in Bacterial Physiology and Virulence

Neville

Roberge

Jia

2022

IJMS

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“…Extracellular polyP at concentrations ranging from 5 to 15 μg/ml, which correspond to the concentrations of polyP in medium cell density cultures, inhibit the killing of ingested Escherichia coli ( E. coli ) in D. discoideum cells without significantly affecting the ingestion of E. coli or fluorescently labeled heat-killed yeast (zymosan) bioparticles (Rijal et al, 2020). As previously observed for 15 μg/ml polyP, 47, 470, and 705 μg/ml polyP inhibited the killing of ingested E. coli by D. discoideum cells at 24 hours after ingestion (Figure S1I).…”

Section: Resultsmentioning

confidence: 99%

Dictyostelium discoideum cells sense their local density and retain nutrients when the cells are about to overgrow their food source

Rijal

Kirolos

Rahman

et al. 2022

Preprint

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Dictyostelium discoideum is a unicellular eukaryote that eats bacteria, and eventually overgrows the bacteria. D. discoideum cells accumulate extracellular polyphosphate (polyP), and the polyP concentration increases as the local cell density increases. At high cell densities, the correspondingly high extracellular polyP concentrations allow cells to sense that they are about to overgrow their food supply and starve, causing the D. discoideum cells to inhibit their proliferation. In this report, we show that high extracellular polyP inhibits exocytosis of undigested or partially digested nutrients. PolyP decreases cell membrane fluidity and plasma membrane recycling, and this requires the G protein-coupled polyP receptor GrlD, the polyphosphate kinase Ppk1, and the inositol hexakisphosphate kinase I6kA. PolyP did not affect random cell motility, cell speed, or F-actin levels. PolyP decreased membrane saturated fatty acids and altered lipid and protein contents in detergent-insoluble lipid microdomains. Together, these data suggest that D. discoideum cells use polyP as a signal to sense their local cell density and reduce cell membrane fluidity and membrane recycling, perhaps as a mechanism to retain ingested food when the cells are about to starve.

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“…It has already been demonstrated that polyP shows biological effects in a chain length-dependent manner (Angelova et al, 2016). Indeed, bacterial long-chain polyP has been shown to potentiate pathogenicity by inhibiting phagosome maturation (Roewe et al, 2020) and interfering with macrophage function (Rijal et al, 2020). Therefore, it is suggested that the response of polyP to inflammation will be different depending on the dose and degree of polymerization.…”

Section: Discussionmentioning

confidence: 99%

Inorganic polyphosphate modulates leukocyte accumulation and vascular endothelial cell permeability and ameliorates cecal ligation and puncture-induced lethality

Yamazaki

Terashima-Hasegawa

Manabe

et al. 2021

Fundam. Toxicol. Sci.

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Inorganic polyphosphates with an average degree of polymerization of 150 (polyP 150 ) have been shown to improve mortality in a lipopolysaccharide model of sepsis in mice. We aimed to investigate the effects of polyP 150 in a mouse model of cecal ligation and puncture (CLP) peritonitis, which accurately reflects clinical sepsis, and elucidate its mechanism of action and suitability as a candidate for sepsis treatment. The present study demonstrated that treatment with polyP 150 significantly improved survival rate in mouse model of CLP peritonitis. polyP 150 inhibited a CLP-mediated increase in pulmonary vascular permeability as demonstrated by Evans blue dye assay. Pretreatment of polyP 150 in human vascular endothelial cells, HMEC-1 cells, showed inhibition of tumor necrosis factor-α-induced monocytic THP-1 cell adhesion and intercellular adhesion molecule 1/CD54 gene expression. These results suggest that polyP 150 ameliorates fatal sepsis by inhibiting expression of the cell adhesion molecule and the accumulation of leukocytes in the vascular endothelium, thereby suppressing the increase in vascular permeability. Our results in this study suggest that polyP 150 could be a candidate for novel sepsis treatments.

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Polyphosphate is an extracellular signal that can facilitate bacterial survival in eukaryotic cells

Cited by 38 publications

References 91 publications

Polyphosphate Kinase 2 (PPK2) Enzymes: Structure, Function, and Roles in Bacterial Physiology and Virulence

Polyphosphate Kinase 2 (PPK2) Enzymes: Structure, Function, and Roles in Bacterial Physiology and Virulence

Dictyostelium discoideum cells sense their local density and retain nutrients when the cells are about to overgrow their food source

Inorganic polyphosphate modulates leukocyte accumulation and vascular endothelial cell permeability and ameliorates cecal ligation and puncture-induced lethality

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