Gene

Point mutation

Cell biology

World Wide Web

Artemisinin

Malaria

Biology

Parasite hosting

Compartment (ship)

Receptor

Mutation

Hemoglobin

Biochemistry

Computer science

Plasmodium falciparum

Geology

Endocytosis

Oceanography

Immunology

Genetics

Plasmodium (life cycle)

Cell

Endocytic cycle

Science

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.

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