| Literature DB >> 31896710 |
Jakob Birnbaum1, Sarah Scharf1, Sabine Schmidt1, Ernst Jonscher1, Wieteke Anna Maria Hoeijmakers2, Sven Flemming1, Christa Geeke Toenhake2, Marius Schmitt1, Ricarda Sabitzki1, Bärbel Bergmann1, Ulrike Fröhlke1, Paolo Mesén-Ramírez1, Alexandra Blancke Soares1, Hendrik Herrmann1, Richárd Bártfai2, Tobias Spielmann3.
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.Entities:
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Year: 2020 PMID： 31896710 DOI： 10.1126/science.aax4735
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728