A druggable oxidative folding pathway in the endoplasmic reticulum of human malaria parasites

Malaria remains a major global health problem, and there exists a constant need to identify druggable weaknesses in P. falciparum biology. The endoplasmic reticulum (ER) has many essential roles in the asexual lifecycle and may offer new drug targets, but it remains critically understudied. We generated conditional mutants of the putative redox-active, ER chaperone Pf J2, and show that it is essential for parasite survival. Using a redox-active cysteine crosslinker, we identify its substrates to be other mediators of oxidative folding, Pf PDI8 and Pf PDI11, suggesting a redox-regulatory role for Pf J2. Knockdown of these protein disulfide isomerases in Pf J2 conditional mutants show that Pf PDI11 is not essential, while Pf PDI8 is essential for asexual growth and may work in a complex with PfJ2 and other ER chaperones. Finally, we show that these redox interactions in the parasite ER are sensitive to small molecule inhibition. Together these data build a model for how oxidative folding occurs in the P. falciparum ER and demonstrate its suitability for antimalarial drug development.