气候变化领域集成服务门户(CCPortal): A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites

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DOI	10.1126/science.aax4735
	A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites
	Birnbaum J.; Scharf S.; Schmidt S.; Jonscher E.; Maria Hoeijmakers W.A.; Flemming S.; Toenhake C.G.; Schmitt M.; Sabitzki R.; Bergmann B.; Fröhlke U.; Mesén-Ramírez P.; Soares A.B.; Herrmann H.; Bártfai R.; Spielmann T.
发表日期	2020
ISSN	0036-8075
起始页码	51
结束页码	59
卷号	367 期号:6473
英文摘要	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. © 2020 American Association for the Advancement of Science. All rights reserved.
关键词	artemisinin artemisinin derivative cytosol receptor hemoglobin protein Kelch13 protozoal protein unclassified drug antimalarial agent cell drug resistance hemoglobin malaria mutation physiology protein antimalarial drug resistance Article controlled study endocytosis gene inactivation gene mutation host cell Kelch13 gene nonhuman Plasmodium priority journal protein analysis protein function
语种	英语
来源机构	Science
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/133812
推荐引用方式 GB/T 7714	Birnbaum J.,Scharf S.,Schmidt S.,et al. A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites[J]. Science,2020,367(6473).
APA	Birnbaum J..,Scharf S..,Schmidt S..,Jonscher E..,Maria Hoeijmakers W.A..,...&Spielmann T..(2020).A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites.,367(6473).
MLA	Birnbaum J.,et al."A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites".367.6473(2020).