A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31896710.
- Also identified by DOI 10.1126/science.aax4735.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
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.
Medical subject headings
- Antimalarials
- Artemisinins
- Drug Resistance
- Endocytosis
- Malaria, Falciparum
- Plasmodium falciparum
- Protozoan Proteins