Ca(2+) signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG.
Ca(2+) signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG.
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疟疾寄生虫中对排出和配子发生至关重要的Ca（2+）信号依赖于与PKG相互作用的多通道膜蛋白。
DOI：
10.1126/sciadv.abe5396
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发表时间：
2021-03
期刊：
影响因子：
13.6
通讯作者：
Brochet M
中科院分区：
文献类型：
--
作者：
Balestra AC;Koussis K;Klages N;Howell SA;Flynn HR;Bantscheff M;Pasquarello C;Perrin AJ;Brusini L;Arboit P;Sanz O;Castaño LP;Withers-Martinez C;Hainard A;Ghidelli-Disse S;Snijders AP;Baker DA;Blackman MJ;Brochet M
一种膜蛋白与PKG相互作用，并在疟疾寄生虫的多个生命周期阶段调节钙信号。cgmp依赖性蛋白激酶（PKG）调控的钙信号传导控制着疟原虫关键的生命周期转变。然而，在缺乏典型钙通道的疟原虫中，钙是如何从细胞内储存中动员的尚不清楚。在这里，我们发现了一种多通道膜蛋白ICM1，它与转运蛋白和钙通道同源，在无性血液阶段和传播阶段都与PKG密切相关。磷酸化蛋白质组学分析显示多个ICM1磷酸化事件依赖于PKG活性。柏氏疟原虫ICM1在特定阶段的耗尽会阻碍细胞内钙动员，从而阻止配子体形成，而恶性疟原虫ICM1的有条件缺失对寄生虫有害，导致钙动员严重减少、出口缺陷和缺乏入侵。我们的研究结果表明，ICM1是转导pkg依赖性信号的关键缺失环节，并为疟疾寄生虫的非典型钙稳态提供了以前未知的见解，这对病理和疾病传播至关重要。
A membrane protein interacts with PKG and regulates calcium signals at multiple lifecycle stages in malaria parasites. Calcium signaling regulated by the cGMP-dependent protein kinase (PKG) controls key life cycle transitions in the malaria parasite. However, how calcium is mobilized from intracellular stores in the absence of canonical calcium channels in Plasmodium is unknown. Here, we identify a multipass membrane protein, ICM1, with homology to transporters and calcium channels that is tightly associated with PKG in both asexual blood stages and transmission stages. Phosphoproteomic analyses reveal multiple ICM1 phosphorylation events dependent on PKG activity. Stage-specific depletion of Plasmodium berghei ICM1 prevents gametogenesis due to a block in intracellular calcium mobilization, while conditional loss of Plasmodium falciparum ICM1 is detrimental for the parasite resulting in severely reduced calcium mobilization, defective egress, and lack of invasion. Our findings suggest that ICM1 is a key missing link in transducing PKG-dependent signals and provide previously unknown insights into atypical calcium homeostasis in malaria parasites essential for pathology and disease transmission.
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