A Phosphoinositide-Binding Protein Acts in the Trafficking Pathway of Hemoglobin in the Malaria Parasite Plasmodium falciparum

0556518 - BC 2023 RIV US eng J - Journal Article
Mukherjee, A. - Crochetiere, M. - Sergerie, A. - Amiar, S. - Thompson, L.A. - Ebrahimzadeh, Z. - Gagnon, D. - Lauruol, F. - Bourgeois, A. - Galaup, T. - Roucheray, S. - Hallee, S. - Padmanabhan, P. - Stahelin, R. - Dacks, Joel Bryan - Richard, D.
A Phosphoinositide-Binding Protein Acts in the Trafficking Pathway of Hemoglobin in the Malaria Parasite Plasmodium falciparum.
mBio. Roč. 13, č. 1 (2022), č. článku e03239-21. ISSN 2161-2129. E-ISSN 2150-7511
Institutional support: RVO:60077344
Keywords : artemisinin resistance * food vacuole * phosphatidylinositol synthase * molecular-mechanism * tethering complexes * membrane-fusion * metabolism * hydrolysis * kinase * lipids * hemoglobin * knockout * malaria * phosphoinositides * vacuoles * vesicular trafficking
OECD category: Microbiology
Impact factor: 6.4, year: 2022
Method of publishing: Open access
https://journals.asm.org/doi/10.1128/mbio.03239-21

Phosphoinositide lipids play key roles in a variety of processes in eukaryotic cells, but our understanding of their functions in the malaria parasite Plasmodium falciparum is still very much limited. To gain a deeper comprehension of the roles of phosphoinositides in this important pathogen, we attempted gene inactivation for 24 putative effectors of phosphoinositide metabolism. Our results reveal that 79% of the candidates are refractory to genetic deletion and are therefore potentially essential for parasite growth. Inactivation of the gene coding for a Plasmodium-specific putative phosphoinositide-binding protein, which we named PfPX1, results in a severe growth defect. We show that PfPX1 likely binds phosphatidylinositol-3-phosphate and that it localizes to the membrane of the digestive vacuole of the parasite and to vesicles filled with host cell cytosol and labeled with endocytic markers. Critically, we provide evidence that it is important in the trafficking pathway of hemoglobin from the host erythrocyte to the digestive vacuole. Finally, inactivation of PfPX1 renders parasites resistant to artemisinin, the frontline antimalarial drug. Globally, the minimal redundancy in the putative phosphoinositide proteins uncovered in our work supports that targeting this pathway has potential for antimalarial drug development. Moreover, our identification of a phosphoinositide-binding protein critical for the trafficking of hemoglobin provides key insight into this essential process.
Permanent Link: https://hdl.handle.net/11104/0340141