Roles of Ferredoxin-Dependent Proteins in the Apicoplast of Plasmodium falciparum Parasites.
Roles of Ferredoxin-Dependent Proteins in the Apicoplast of Plasmodium falciparum Parasites.
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DOI：
10.1128/mbio.03023-21
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发表时间：
2021-02-22
期刊：
影响因子：
6.4
通讯作者：
Prigge ST
中科院分区：
文献类型：
--
作者：
Swift RP;Rajaram K;Elahi R;Liu HB;Prigge ST
铁氧还蛋白(FD)和铁氧还蛋白-NADP+还原酶(FNR)形成一个氧化还原系统，该系统被认为在疟疾寄生虫顶体细胞器的维持和功能中发挥核心作用。Fd/FNR系统为质外体中各种依赖于铁硫簇(FeS)的蛋白质提供还原能力，被认为有助于维持细胞器中的氧化还原平衡。虽然Fd/FNR系统一直是抗疟疾药物开发的靶点，但Fd、FNR和FES蛋白可能依赖于它们的还原能力在寄生虫的生存和质膜维持中发挥着未知的作用。为了解决这些问题，我们在一个含有质外体旁路系统的寄生虫系中产生了这些蛋白质的遗传缺失。通过这些缺失，我们发现Fd、FNR和某些FES蛋白是寄生虫生存所必需的，但我们发现这些蛋白都不是维持质外体所必需的。此外，我们还通过删除FES转移蛋白Sufa和NfuApi，解决了Fd及其下游FES蛋白如何获得FES辅因子的问题。虽然这些蛋白的单独缺失揭示了它们的可有可无，但双重缺失导致了合成致死性，表明在为Fd和其他必需的FES蛋白提供FES簇方面发挥了多余的作用。我们的数据支持这样一个模型，即Fd/FNR系统对某些下游FES蛋白的还原能力对血期疟疾寄生虫的生存是必不可少的，但对细胞器的维持不是必需的，而其他FES蛋白对寄生虫发育的这一阶段是必不可少的。
Ferredoxin (Fd) and ferredoxin-NADP+ reductase (FNR) form a redox system that is hypothesized to play a central role in the maintenance and function of the apicoplast organelle of malaria parasites. The Fd/FNR system provides reducing power to various iron-sulfur cluster (FeS)-dependent proteins in the apicoplast and is believed to help to maintain redox balance in the organelle. While the Fd/FNR system has been pursued as a target for antimalarial drug discovery, Fd, FNR, and the FeS proteins presumably reliant on their reducing power play an unknown role in parasite survival and apicoplast maintenance. To address these questions, we generated genetic deletions of these proteins in a parasite line containing an apicoplast bypass system. Through these deletions, we discovered that Fd, FNR, and certain FeS proteins are essential for parasite survival but found that none are required for apicoplast maintenance. Additionally, we addressed the question of how Fd and its downstream FeS proteins obtain FeS cofactors by deleting the FeS transfer proteins SufA and NfuApi. While individual deletions of these proteins revealed their dispensability, double deletion resulted in synthetic lethality, demonstrating a redundant role in providing FeS clusters to Fd and other essential FeS proteins. Our data support a model in which the reducing power from the Fd/FNR system to certain downstream FeS proteins is essential for the survival of blood-stage malaria parasites but not for organelle maintenance, while other FeS proteins are dispensable for this stage of parasite development.
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影响因子：
6.7
作者：
Biddau M;Bouchut A;Major J;Saveria T;Tottey J;Oka O;van-Lith M;Jennings KE;Ovciarikova J;DeRocher A;Striepen B;Waller RF;Parsons M;Sheiner L
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Sheiner L
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作者：
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影响因子：
3.2
作者：
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通讯作者：
Winkler, ME
影响因子：
3.7
作者：
Haussig, Joana M.;Matuschewski, Kai;Kooij, Taco W. A.
通讯作者：
Kooij, Taco W. A.