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 language | English (US) |
|---|---|
| Article number | e40529 |
| Journal | eLife |
| Volume | 8 |
| DOIs | |
| State | Published - Mar 2019 |
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All Science Journal Classification (ASJC) codes
- Neuroscience(all)
- Immunology and Microbiology(all)
- Biochemistry, Genetics and Molecular Biology(all)
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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, 03.2019.Research output: Contribution to journal › Article
TY - JOUR
T1 - Plasmodium niemann-pick type C1- related protein is a druggable target required for parasite membrane homeostasis
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
Y1 - 2019/3
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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=85063291544&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063291544&partnerID=8YFLogxK
U2 - 10.7554/eLife.40529
DO - 10.7554/eLife.40529
M3 - Article
C2 - 30888318
AN - SCOPUS:85063291544
VL - 8
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e40529
ER -