Plasmodium niemann-pick type C1- related protein is a druggable target required for parasite membrane homeostasis

Eva S. Istvan, Sudipta Das, Suyash Bhatnagar, Josh R. Beck, Edward Owen, Manuel Llinas, Suresh M. Ganesan, Jacquin C. Niles, Elizabeth Winzeler, Akhil B. Vaidya, Daniel E. Goldberg

Research output: Contribution to journalArticle

Abstract

Plasmodium parasites possess a protein with homology to Niemann-Pick Type C1 proteins (Niemann-Pick Type C1-Related protein, NCR1). We isolated parasites with resistance- conferring mutations in Plasmodium falciparum NCR1 (PfNCR1) during selections with three diverse small-molecule antimalarial compounds and show that the mutations are causative for compound resistance. PfNCR1 protein knockdown results in severely attenuated growth and confers hypersensitivity to the compounds. Compound treatment or protein knockdown leads to increased sensitivity of the parasite plasma membrane (PPM) to the amphipathic glycoside saponin and engenders digestive vacuoles (DVs) that are small and malformed. Immuno-electron microscopy and split-GFP experiments localize PfNCR1 to the PPM. Our experiments show that PfNCR1 activity is critically important for the composition of the PPM and is required for DV biogenesis, suggesting PfNCR1 as a novel antimalarial drug target. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor’s assessment is that all the issues have been addressed (see decision letter).

Original languageEnglish (US)
Article numbere40529
JournaleLife
Volume8
DOIs
StatePublished - Mar 1 2019

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Plasmodium
Plasmodium falciparum
Parasites
Homeostasis
Membranes
Cell membranes
Cell Membrane
Antimalarials
Vacuoles
Proteins
Mutation
Peer Review
Immunoelectron Microscopy
Saponins
Glycosides
Electron microscopy
Hypersensitivity
Experiments
Molecules
Growth

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Istvan, Eva S. ; Das, Sudipta ; Bhatnagar, Suyash ; Beck, Josh R. ; Owen, Edward ; Llinas, Manuel ; Ganesan, Suresh M. ; Niles, Jacquin C. ; Winzeler, Elizabeth ; Vaidya, Akhil B. ; Goldberg, Daniel E. / Plasmodium niemann-pick type C1- related protein is a druggable target required for parasite membrane homeostasis. In: eLife. 2019 ; Vol. 8.
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abstract = "Plasmodium parasites possess a protein with homology to Niemann-Pick Type C1 proteins (Niemann-Pick Type C1-Related protein, NCR1). We isolated parasites with resistance- conferring mutations in Plasmodium falciparum NCR1 (PfNCR1) during selections with three diverse small-molecule antimalarial compounds and show that the mutations are causative for compound resistance. PfNCR1 protein knockdown results in severely attenuated growth and confers hypersensitivity to the compounds. Compound treatment or protein knockdown leads to increased sensitivity of the parasite plasma membrane (PPM) to the amphipathic glycoside saponin and engenders digestive vacuoles (DVs) that are small and malformed. Immuno-electron microscopy and split-GFP experiments localize PfNCR1 to the PPM. Our experiments show that PfNCR1 activity is critically important for the composition of the PPM and is required for DV biogenesis, suggesting PfNCR1 as a novel antimalarial drug target. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor’s assessment is that all the issues have been addressed (see decision letter).",
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Istvan, ES, Das, S, Bhatnagar, S, Beck, JR, Owen, E, Llinas, M, Ganesan, SM, Niles, JC, Winzeler, E, Vaidya, AB & Goldberg, DE 2019, 'Plasmodium niemann-pick type C1- related protein is a druggable target required for parasite membrane homeostasis', eLife, vol. 8, e40529. https://doi.org/10.7554/eLife.40529

Plasmodium niemann-pick type C1- related protein is a druggable target required for parasite membrane homeostasis. / Istvan, Eva S.; Das, Sudipta; Bhatnagar, Suyash; Beck, Josh R.; Owen, Edward; Llinas, Manuel; Ganesan, Suresh M.; Niles, Jacquin C.; Winzeler, Elizabeth; Vaidya, Akhil B.; Goldberg, Daniel E.

In: eLife, Vol. 8, e40529, 01.03.2019.

Research output: Contribution to journalArticle

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AU - Istvan, Eva S.

AU - Das, Sudipta

AU - Bhatnagar, Suyash

AU - Beck, Josh R.

AU - Owen, Edward

AU - Llinas, Manuel

AU - Ganesan, Suresh M.

AU - Niles, Jacquin C.

AU - Winzeler, Elizabeth

AU - Vaidya, Akhil B.

AU - Goldberg, Daniel E.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Plasmodium parasites possess a protein with homology to Niemann-Pick Type C1 proteins (Niemann-Pick Type C1-Related protein, NCR1). We isolated parasites with resistance- conferring mutations in Plasmodium falciparum NCR1 (PfNCR1) during selections with three diverse small-molecule antimalarial compounds and show that the mutations are causative for compound resistance. PfNCR1 protein knockdown results in severely attenuated growth and confers hypersensitivity to the compounds. Compound treatment or protein knockdown leads to increased sensitivity of the parasite plasma membrane (PPM) to the amphipathic glycoside saponin and engenders digestive vacuoles (DVs) that are small and malformed. Immuno-electron microscopy and split-GFP experiments localize PfNCR1 to the PPM. Our experiments show that PfNCR1 activity is critically important for the composition of the PPM and is required for DV biogenesis, suggesting PfNCR1 as a novel antimalarial drug target. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor’s assessment is that all the issues have been addressed (see decision letter).

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