Inorganic phosphate uptake in Trypanosoma cruzi is coupled to K+ cycling and to active Na+ extrusion

Dick, Claudia F.; Dos-Santos, André L.A.; Majerowicz, David; Paes, Lisvane Silva; Giarola, Naira Lígia Lima; Gondim, Kátia C.; Vieyra, Adalberto; Meyer-Fernandes, J.R.

doi:10.1016/j.bbagen.2013.04.034

Cited by 21 publications

(27 citation statements)

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“…A). It has been reported that proliferation of epimastigotes under limiting P i conditions is slower (Dick et al ., ), and we therefore investigated whether knockdown and TcPho91‐GFP‐OE parasites were more affected under those conditions. We compared growth of mutant and wild‐type parasites in semi‐defined medium 79 (SDM‐79) supplemented with putrescine, a medium used before for growing T. cruzi (Hasne et al ., ) that contains 5 mM P i instead of 55 mM P i present in LIT medium.…”

Section: Resultsmentioning

confidence: 99%

“…A Na + /Pi symporter has also been characterized in the malaria parasite, Plasmodium falciparum (Saliba et al, 2006). Pi transport has been described in T. cruzi (De Boiso and Stoppani, 1972;Dick et al, 2013), and several sequences with characteristics of Pi transporters are present in its genome. Phosphate transport and partial sequences corresponding to phosphate transporters of Trypanosoma rangeli (Dick et al, 2012) and Leishmania infantum (Russo-Abrahao et al, 2013) have also been reported.…”

Section: Discussionmentioning

confidence: 99%

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TcPho91 is a contractile vacuole phosphate sodium symporter that regulates phosphate and polyphosphate metabolism in Trypanosoma cruzi

Jiménez

Docampo

2015

Molecular Microbiology

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Summary We have identified a phosphate transporter (TcPho91) localized to the bladder of the contractile vacuole complex (CVC) of Trypanosoma cruzi, the etiologic agent of Chagas disease. TcPho91 has 12 transmembrane domains, an N-terminal regulatory SPX domain and an anion permease domain. Functional expression in Xenopus laevis oocytes followed by two-electrode voltage clamp showed that TcPho91 is a low affinity transporter with a Km for Pi in the millimolar range, and sodium-dependency. Epimastigotes overexpressing TcPho91-GFP have significantly higher levels of pyrophosphate (PPi) and short chain polyphosphate (polyP), suggesting accumulation of Pi in these cells. Moreover, when overexpressing parasites were maintained in a medium with low Pi, they grew at higher rates than control parasites. Only one allele of TcPho91 in the CL strain encodes for the complete open reading frame, while the other one is truncated encoding for only the N-terminal domain. Taking advantage of this characteristic, knockdown experiments were performed resulting in cells with reduced growth rate as well as a reduction in PPi and short-chain polyP levels. Our results indicate that TcPho91 is a phosphate sodium symporter involved in Pi homeostasis in T. cruzi.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TcPho91 is a contractile vacuole phosphate sodium symporter that regulates phosphate and polyphosphate metabolism in Trypanosoma cruzi

Jiménez

Docampo

2015

Molecular Microbiology

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“…This inhibitory effect may indicate a role of sodium into the intricate mode of purine control in these parasites. In fact, it was recently demonstrated that inorganic phosphate transport across the plasma membrane of several parasites depends on the respective sodium co-transport (Dick et al, 2013) and therefore, sodium intracellular concentration must be tightly controlled. Since inorganic phosphate assimilation by the cell impacts directly the synthesis/degradation of phosphorylated compounds, it seems there is a correlation between the observed events that require deeper investigation.…”

Section: Discussionmentioning

confidence: 99%

Kinetic and biochemical characterization of Trypanosoma evansi nucleoside triphosphate diphosphohydrolase

Weiss

Batista

Wagner

et al. 2015

Experimental Parasitology

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“…Significantly, Leishmania infantum , an intracellular parasitic agent of human visceral leishmaniasis which is a neglected tropical disease of 12 million people (10), expresses a Pi transporter homologous to the Saccharomyces cerevisiae high-affinity H+-Pi symporter Pho84 as its major mode of Pi acquisition (11). Insect stages of the related kinetoplastid parasite Trypanosoma cruzi , the agent of Chagas disease estimated to chronically infect 8 million people while leading to inexorable cardiac death in 20-30% of the infected (12, 13), are Pi-dependent for their cellular differentiation (14). T. cruzi insect stages utilize homologs of the Saccharomyces cerevisiae high- and low-affinity Pi importers to acquire the Pi quantities that permit their development and proliferation (14).…”

Section: Introductionmentioning

confidence: 99%

“…Insect stages of the related kinetoplastid parasite Trypanosoma cruzi , the agent of Chagas disease estimated to chronically infect 8 million people while leading to inexorable cardiac death in 20-30% of the infected (12, 13), are Pi-dependent for their cellular differentiation (14). T. cruzi insect stages utilize homologs of the Saccharomyces cerevisiae high- and low-affinity Pi importers to acquire the Pi quantities that permit their development and proliferation (14).…”

Section: Introductionmentioning

confidence: 99%

Intersection of phosphate transport, oxidative stress and TOR signalling inCandida albicansvirulence

Liu

Uppuluri

Broggi

et al. 2018

Preprint

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70Phosphate is an essential macronutrient required for cell growth and division. Pho84 is the 71 major high-affinity cell-surface phosphate importer of Saccharomyces cerevisiae and a crucial 72 element in the phosphate homeostatic system of this model yeast. We found that loss of 73Candida albicans Pho84 attenuated virulence in Drosophila and murine oropharyngeal and 74 disseminated models of invasive infection, and conferred hypersensitivity to neutrophil killing. 75Susceptibility of cells lacking Pho84 to neutrophil attack depended on reactive oxygen species 76 (ROS): pho84-/-cells were no more susceptible than wild type C. albicans to neutrophils from 77 a patient with chronic granulomatous disease, or to those whose oxidative burst was 78 pharmacologically inhibited or neutralized. pho84-/-mutants hyperactivated oxidative stress 79 signalling. They accumulated intracellular ROS in the absence of extrinsic oxidative stress, in 80 high as well as low ambient phosphate conditions. ROS accumulation correlated with 81 diminished levels of the unique superoxide dismutase Sod3 in pho84-/-cells, while SOD3 82 overexpression from a conditional promoter substantially restored these cells' oxidative stress 83 resistance in vitro. Repression of SOD3 expression sharply increased their oxidative stress 84 hypersensitivity. Neither of these oxidative stress management effects of manipulating SOD3 85 transcription was observed in PHO84 wild type cells. Sod3 levels were not the only factor 86 driving oxidative stress effects on pho84-/-cells, though, because overexpressing SOD3 did 87 not ameliorate these cells' hypersensitivity to neutrophil killing ex vivo, indicating Pho84 has 88 further roles in oxidative stress resistance and virulence. Measurement of cellular metal 89 concentrations demonstrated that diminished Sod3 expression was not due to decreased 90 import of its metal cofactor manganese, as predicted from the function of S. cerevisiae Pho84 91 as a low-affinity manganese transporter. Instead of a role of Pho84 in metal transport, we 92 found its role in TORC1 activation to impact oxidative stress management: overexpression of 93 the TORC1-activating GTPase Gtr1 relieved the Sod3 deficit and ROS excess in pho84-/-null 94 mutant cells, though it did not suppress their hypersensitivity to neutrophil killing or hyphal 95 growth defect. Pharmacologic inhibition of Pho84 by small molecules including the FDA-96 approved drug foscarnet also induced ROS accumulation. Inhibiting Pho84 could hence 97 support host defenses by sensitizing C. albicans to oxidative stress. 98 99 100 Author Summary 101 102Candida albicans is the species most often isolated from patients with invasive fungal disease, 103 and is also a common colonizer of healthy people. It is well equipped to compete for nutrients 104 with bacteria co-inhabiting human gastrointestinal mucous membranes, since it possesses 105 multiple transporters to internalize important nutrients like sugars, nitrogen sources, and 106 phosphate. During infection, the fungus needs...

show abstract

Inorganic phosphate uptake in Trypanosoma cruzi is coupled to K+ cycling and to active Na+ extrusion

Cited by 21 publications

References 47 publications

TcPho91 is a contractile vacuole phosphate sodium symporter that regulates phosphate and polyphosphate metabolism in Trypanosoma cruzi

TcPho91 is a contractile vacuole phosphate sodium symporter that regulates phosphate and polyphosphate metabolism in Trypanosoma cruzi

Kinetic and biochemical characterization of Trypanosoma evansi nucleoside triphosphate diphosphohydrolase

Intersection of phosphate transport, oxidative stress and TOR signalling inCandida albicansvirulence

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