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A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites
Science ( IF 56.9 ) Pub Date : 2020-01-02 , DOI: 10.1126/science.aax4735
Jakob Birnbaum 1 , Sarah Scharf 1 , Sabine Schmidt 1 , Ernst Jonscher 1 , Wieteke Anna Maria Hoeijmakers 2 , Sven Flemming 1 , Christa Geeke Toenhake 2 , Marius Schmitt 1 , Ricarda Sabitzki 1 , Bärbel Bergmann 1 , Ulrike Fröhlke 1 , Paolo Mesén-Ramírez 1 , Alexandra Blancke Soares 1 , Hendrik Herrmann 1 , Richárd Bártfai 2 , Tobias Spielmann 1
Affiliation  

An artemisinin resistance mechanism Species of the malaria parasite Plasmodium live in red blood cells and possess a highly conserved gene called kelch13. Single point mutations in this gene are associated with resistance to the frontline artemisinin drugs. Birnbaum et al. found that Kelch13 and associated proteins comprise an endocytic compartment associated with feeding on host erythrocytes (see the Perspective by Marapana and Cowman). Hot targets for artemisinin research also occur in this compartment, including the proteins UBP1, AP-2µ, and the parasite homolog of the endocytosis protein Eps15. Inactivation of Kelch13 compartment proteins revealed that these are required for endocytosis of host hemoglobin. Artemisinins are activated by hemoglobin degradation products, so these mutations render the parasite resistant to these drugs to different extents. Science, this issue p. 51; see also p. 22 The function of a highly conserved parasite protein and its role in drug resistance are defined. 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.

中文翻译:

Kelch13 定义的内吞通路介导疟疾寄生虫的青蒿素抗性

一种青蒿素抗性机制 疟原虫 疟原虫 生活在红细胞中,并拥有一个称为 kelch13 的高度保守基因。该基因的单点突变与对一线青蒿素药物的耐药性有关。伯恩鲍姆等人。发现 Kelch13 和相关蛋白质包含一个与以宿主红细胞为食的内吞隔室(参见 Marapana 和 Cowman 的观点)。青蒿素研究的热门目标也出现在这个隔间中,包括蛋白质 UBP1、AP-2µ 和内吞作用蛋白质 Eps15 的寄生虫同源物。Kelch13 隔室蛋白的失活表明这些是宿主血红蛋白内吞作用所必需的。青蒿素被血红蛋白降解产物激活,所以这些突变使寄生虫在不同程度上对这些药物产生抗药性。科学,这个问题 p。51; 另见第。22 定义了高度保守的寄生虫蛋白的功能及其在耐药性中的作用。青蒿素及其衍生物 (ARTs) 是抗疟疾的一线药物,但耐药性正在危及其有效性。ART 抗性是由寄生虫 Kelch13 蛋白的突变介导的,但 Kelch13 的功能及其在抗性中的作用仍不清楚。在这项研究中,我们确定了位于 Kelch13 定义的隔室中的蛋白质。其中包括 Kelch13 在内的 8 种蛋白质的失活使寄生虫对 ART 产生抗性,揭示了对抗性至关重要的途径。功能分析表明,这些蛋白质是宿主细胞内吞血红蛋白所必需的。具有灭活 Kelch13 或产生抗性的 Kelch13 突变的寄生虫显示血红蛋白内吞作用降低。ARTs 被血红蛋白的降解产物激活。因此,降低 Kelch13 及其相互作用物的活性会减少血红蛋白内吞作用,从而减少 ART 激活,导致寄生虫抗性。
更新日期:2020-01-02
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