@article{75b00d3866544989be6a586a2c6ff752,
title = "Plasmodium niemann-pick type C1- related protein is a druggable target required for parasite membrane homeostasis",
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{\textquoteright}s assessment is that all the issues have been addressed (see decision letter).",
author = "Istvan, {Eva S.} and Sudipta Das and Suyash Bhatnagar and Beck, {Josh R.} and Edward Owen and Manuel Llinas and Ganesan, {Suresh M.} and Niles, {Jacquin C.} and Elizabeth Winzeler and Vaidya, {Akhil B.} and Goldberg, {Daniel E.}",
note = "Funding Information: We are thankful to our MalDA Consortium collaborators and DS Ory (WU) for stimulating discussions, AS Nasamu and A Polino for valuable suggestions, B Vaupel for assistance during cloning, W Beatty for electron microscopy, LD Sibley for use of the spinning-disk confocal microscope and M Lee, M Carrasquilla and J Rayner for consulting on the Rh3 gRNA design. This work was supported by Gates Foundation Grants OPP 1054480 (Winzeler, Goldberg, Llin{\'a}s), OPP1132313 (Niles), and NIH grants R01AI098413 and R01AI132508 (Vaidya); K99/R00 HL133453 (Beck), and 1DP2OD007124 (Niles). Funding Information: We are thankful to our MalDA Consortium collaborators and DS Ory (WU) for stimulating discus- sions, AS Nasamu and A Polino for valuable suggestions, B Vaupel for assistance during cloning, W Beatty for electron microscopy, LD Sibley for use of the spinning-disk confocal microscope and M Lee, M Carrasquilla and J Rayner for consulting on the Rh3 gRNA design. This work was supported by Gates Foundation Grants OPP 1054480 (Winzeler, Goldberg, Llin{\'a}s), OPP1132313 (Niles), and NIH grants R01AI098413 and R01AI132508 (Vaidya); K99/R00 HL133453 (Beck), and 1DP2OD007124 (Niles). National Institute of Allergy and Infectious Diseases R01AI132508 National Heart, Lung, and Blood Institute K99/R00 HL133453 Josh R Beck National Institute of Allergy and Infectious Diseases R01AI098413 Akhil B Vaidya. Publisher Copyright: {\textcopyright} Istvan et al.",
year = "2019",
month = mar,
doi = "10.7554/eLife.40529",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}