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Science. 2020 Jan 3;367(6473):51-59. doi: 10.1126/science.aax4735.

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

Author information

1
Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Str. 74, 20359 Hamburg, Germany.
2
Department of Molecular Biology, Radboud University, Geert Grooteplein 26-28, 6525 GA Nijmegen, Netherlands.
3
Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Str. 74, 20359 Hamburg, Germany. spielmann@bnitm.de.
#
Contributed equally

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.

PMID:
31896710
DOI:
10.1126/science.aax4735

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