RT Journal Article
SR Electronic
T1 <em>Plasmodium falciparum</em> Niemann-Pick Type C1-Related Protein is a Druggable Target Required for Parasite Membrane Homeostasis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 371484
DO 10.1101/371484
A1 Istvan, Eva S.
A1 Das, Sudipta
A1 Bhatnagar, Suyash
A1 Beck, Josh R.
A1 Owen, Edward
A1 Llinás, Manuel
A1 Ganesan, Suresh M.
A1 Niles, Jacquin C.
A1 Winzeler, Elizabeth A.
A1 Vaidya, Akhil B.
A1 Goldberg, Daniel E.
YR 2018
UL http://biorxiv.org/content/early/2018/07/18/371484.abstract
AB Plasmodium parasites possess a protein with homology to Niemann-Pick Type C1 proteins (Plasmodium falciparum Niemann-Pick Type C1-Related protein, PfNCR1). We isolated parasites with resistance-conferring mutations in 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.