An intracellular membrane protein GEP1 regulates xanthurenic acid induced gametogenesis of malaria parasites

Nat Commun. 2020 Apr 9;11(1):1764. doi: 10.1038/s41467-020-15479-3.


Gametocytes differentiation to gametes (gametogenesis) within mosquitos is essential for malaria parasite transmission. Both reduction in temperature and mosquito-derived XA or elevated pH are required for triggering cGMP/PKG dependent gametogenesis. However, the parasite molecule for sensing or transducing these environmental signals to initiate gametogenesis remains unknown. Here we perform a CRISPR/Cas9-based functional screening of 59 membrane proteins expressed in the gametocytes of Plasmodium yoelii and identify that GEP1 is required for XA-stimulated gametogenesis. GEP1 disruption abolishes XA-stimulated cGMP synthesis and the subsequent signaling and cellular events, such as Ca2+ mobilization, gamete formation, and gametes egress out of erythrocytes. GEP1 interacts with GCα, a cGMP synthesizing enzyme in gametocytes. Both GEP1 and GCα are expressed in cytoplasmic puncta of both male and female gametocytes. Depletion of GCα impairs XA-stimulated gametogenesis, mimicking the defect of GEP1 disruption. The identification of GEP1 being essential for gametogenesis provides a potential new target for intervention of parasite transmission.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems / genetics
  • Calcium / metabolism
  • Culicidae / metabolism*
  • Culicidae / parasitology
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Gametogenesis / drug effects*
  • Gene Editing / methods
  • Intracellular Membranes / metabolism*
  • Malaria / parasitology
  • Mosquito Vectors / metabolism
  • Mosquito Vectors / parasitology
  • Plasmodium / genetics
  • Plasmodium / metabolism
  • Plasmodium / physiology
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism*
  • Xanthurenates / metabolism
  • Xanthurenates / pharmacology*


  • Protozoan Proteins
  • Xanthurenates
  • xanthurenic acid
  • Cyclic GMP-Dependent Protein Kinases
  • Cyclic GMP
  • Calcium