Research Article

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

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Science  03 Jan 2020:
Vol. 367, Issue 6473, pp. 51-59
DOI: 10.1126/science.aax4735

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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

Abstract

Artemisinin and its derivatives (ARTs) are the frontline drugs against malaria, but resistance is jeopardizing their effectiveness. ART resistance is mediated by mutations in the parasite’s Kelch13 protein, but Kelch13 function and its role in resistance remain unclear. In this study, we identified proteins located at a Kelch13-defined compartment. Inactivation of eight of these proteins, including Kelch13, rendered parasites resistant to ART, revealing a pathway critical for resistance. Functional analysis showed that these proteins are required for endocytosis of hemoglobin from the host cell. Parasites with inactivated Kelch13 or a resistance-conferring Kelch13 mutation displayed reduced hemoglobin endocytosis. ARTs are activated by degradation products of hemoglobin. Hence, reduced activity of Kelch13 and its interactors diminishes hemoglobin endocytosis and thereby ART activation, resulting in parasite resistance.

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