Plasmodium Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis
Name
elife-40529-v2.pdf
Description
Published version
Size
7.09 MB
Format
Adobe PDF
Checksum (MD5)
3c491e0b2d28dd4345fcd5bffe283eb8
Author(s)
Istvan, Eva S
Das, Sudipta
Bhatnagar, Suyash
Beck, Josh R
Owen, Edward
Llinas, Manuel
Maddur Ganesan, Suresh
Niles, Jacquin
Winzeler, Elizabeth
Vaidya, Akhil B
Date Issued
March 2019
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Istvan, Eva S. et al. "Plasmodium Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis." eLife 8 (March 2019): e40529. © 2019 Istvan et al.
Version
Final published version
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).
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Division of Comparative Medicine
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.7554/elife.40529
