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Shelph2, a bacterial-like phosphatase of the malaria parasite Plasmodium falciparum, is dispensable during asexual blood stage.

ABSTRACT: During the erythrocytic cycle of the malaria parasite Plasmodium falciparum, egress and invasion are essential steps finely controlled by reversible phosphorylation. In contrast to the growing number of kinases identified as key regulators, phosphatases have been poorly studied, and calcineurin is the only one identified so far to play a role in invasion. PfShelph2, a bacterial-like phosphatase, is a promising candidate to participate in the invasion process, as it was reported to be expressed late during the asexual blood stage and to reside within an apical compartment, yet distinct from rhoptry bulb, micronemes, or dense granules. It was also proposed to play a role in the control of the red blood cell membrane deformability at the end of the invasion process. However, genetic studies are still lacking to support this hypothesis. Here, we take advantage of the CRISPR-Cas9 technology to tag shelph2 genomic locus while retaining its endogenous regulatory regions. This new strain allows us to follow the endogenous PfShelph2 protein expression and location during asexual blood stages. We show that PfShelph2 apical location is also distinct from the rhoptry neck or exonemes. We further demonstrate PfShelph2 dispensability during the asexual blood stage by generating PfShelph2-KO parasites using CRISPR-Cas9 machinery. Analyses of the mutant during the course of the erythrocytic development indicate that there are no detectable phenotypic consequences of Pfshelph2 genomic deletion. As this lack of phenotype might be due to functional redundancy, we also explore the likelihood of PfShelph1 (PfShelph2 paralog) being a compensatory phosphatase. We conclude that despite its cyclic expression profile, PfShelph2 is a dispensable phosphatase during the Plasmodium falciparum asexual blood stage, whose function is unlikely substituted by PfShelph1.

SUBMITTER: Miliu A

PROVIDER: S-EPMC5658161 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Shelph2, a bacterial-like phosphatase of the malaria parasite Plasmodium falciparum, is dispensable during asexual blood stage.

Miliu Alexandra A Lebrun Maryse M Braun-Breton Catherine C Lamarque Mauld H MH

PloS one 20171026 10

During the erythrocytic cycle of the malaria parasite Plasmodium falciparum, egress and invasion are essential steps finely controlled by reversible phosphorylation. In contrast to the growing number of kinases identified as key regulators, phosphatases have been poorly studied, and calcineurin is the only one identified so far to play a role in invasion. PfShelph2, a bacterial-like phosphatase, is a promising candidate to participate in the invasion process, as it was reported to be expressed l ...[more]

PMID: 29073264

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Project description:BACKGROUND: The carbon metabolism of the blood stages of Plasmodium falciparum, comprising rapidly dividing asexual stages and non-dividing gametocytes, is thought to be highly streamlined, with glycolysis providing most of the cellular ATP. However, these parasitic stages express all the enzymes needed for a canonical mitochondrial tricarboxylic acid (TCA) cycle, and it was recently proposed that they may catabolize glutamine via an atypical branched TCA cycle. Whether these stages catabolize glucose in the TCA cycle and what is the functional significance of mitochondrial metabolism remains unresolved. RESULTS: We reassessed the central carbon metabolism of P. falciparum asexual and sexual blood stages, by metabolically labeling each stage with 13C-glucose and 13C-glutamine, and analyzing isotopic enrichment in key pathways using mass spectrometry. In contrast to previous findings, we found that carbon skeletons derived from both glucose and glutamine are catabolized in a canonical oxidative TCA cycle in both the asexual and sexual blood stages. Flux of glucose carbon skeletons into the TCA cycle is low in the asexual blood stages, with glutamine providing most of the carbon skeletons, but increases dramatically in the gametocyte stages. Increased glucose catabolism in the gametocyte TCA cycle was associated with increased glucose uptake, suggesting that the energy requirements of this stage are high. Significantly, whereas chemical inhibition of the TCA cycle had little effect on the growth or viability of asexual stages, inhibition of the gametocyte TCA cycle led to arrested development and death. CONCLUSIONS: Our metabolomics approach has allowed us to revise current models of P. falciparum carbon metabolism. In particular, we found that both asexual and sexual blood stages utilize a conventional TCA cycle to catabolize glucose and glutamine. Gametocyte differentiation is associated with a programmed remodeling of central carbon metabolism that may be required for parasite survival either before or after uptake by the mosquito vector. The increased sensitivity of gametocyte stages to TCA-cycle inhibitors provides a potential target for transmission-blocking drugs.

Dataset Information

Shelph2, a bacterial-like phosphatase of the malaria parasite Plasmodium falciparum, is dispensable during asexual blood stage.

Publications

Shelph2, a bacterial-like phosphatase of the malaria parasite Plasmodium falciparum, is dispensable during asexual blood stage.

Similar Datasets

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