Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis.

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Journal:
eLife, Volume: 8
Published:
March 19, 2019
PMID:
30888318
Authors:
Eva S Istvan ES, Sudipta Das S, Suyash Bhatnagar S, Josh R Beck JR, Edward Owen E, Manuel Llinas M, Suresh M Ganesan SM, Jacquin C Niles JC, Elizabeth Winzeler E, Akhil B Vaidya AB, Daniel E Goldberg DE
Abstract:

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 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.