A Plasmodium falciparum molecular mechanism of heme binding and sensitivity to artemisinins

Heme is critical to activating artemisinins (ARTs), drugs essential for malaria control. Plasmodium falciparum malaria Kelch13 (K13) binds heme in vitro, but the consequences for in vivo functions remain unknown. As taut regulation of free-heme levels is not feasible in infected erythrocytes, we developed human Du145 cells as a model to study molecular properties of K13 at biological heme concentrations. We show that K13 levels are exquisitely responsive to nanomolar amounts of heme. Heme stabilizes K13 with molecular specificity, raises its oxidative-stress responses and association with autophagic-endosomes. Targeted disruption of lysosomal autophagy further increases K13 levels to fuel ART-induced redox-cell death that is proportional to K13 intensities at physiological heme levels. K13’s kelch-domain confers both heme and ART responsiveness to its mammalian orthologue KEAP1. These data suggest a novel molecular mechanism of K13-heme binding regulating ART-sensitization and power of models to study frontiers of pro-oxidant stress.