A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites

An artemisinin resistance mechanism Species of the malaria parasite Plasmodium live in red blood cells and possess a highly conserved gene called kelch13 . Single point mutations in this gene are associated with resistance to the frontline artemisinin drugs. Birnbaum et al. found that Kelch13 and associated proteins comprise an endocytic compartment associated with feeding on host erythrocytes (see the Perspective by Marapana and Cowman). Hot targets for artemisinin research also occur in this compartment, including the proteins UBP1, AP-2µ, and the parasite homolog of the endocytosis protein Eps15. Inactivation of Kelch13 compartment proteins revealed that these are required for endocytosis of host hemoglobin. Artemisinins are activated by hemoglobin degradation products, so these mutations render the parasite resistant to these drugs to different extents. Science , this issue p. 51 ; see also p. 22