The pathogenesis of human malarial parasite Plasmodium falciparum is interlinked with its timely control of gene expression during its complex life cycle. In this organism, gene expression is partially controlled through epigenetic mechanisms, the regulation of which is, hence, of paramount importance to the parasite. The P. falciparum (Pf)-GCN5 histone acetyltransferase (HAT), an essential enzyme, acetylates histone 3 and regulates global gene expression in the parasite. Here, we show the existence of a novel proteolytic processing for PfGCN5 that is crucial for its activity in vivo We find that a cysteine protease-like enzyme is required for the processing of PfGCN5 protein. Immunofluorescence and immuno-electron microscopy analysis suggest that the processing event occurs in the vicinity of the digestive vacuole of the parasite following its trafficking through the classical ER-Golgi secretory pathway, before it subsequently reaches the nucleus. Furthermore, blocking of PfGCN5 processing leads to the concomitant reduction of its occupancy at the gene promoters and a reduced H3K9 acetylation level at these promoters, highlighting the important correlation between the processing event and PfGCN5 activity. Altogether, our study reveals a unique processing event for a nuclear protein PfGCN5 with unforeseen role of a food vacuolar cysteine protease. This leads to a possibility of the development of new antimalarials against these targets.This article has an associated First Person interview with the first author of the paper.

中文翻译：

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恶性疟原虫GCN5乙酰转移酶遵循一种新的蛋白水解加工途径，这对其功能至关重要。

人类疟疾寄生虫恶性疟原虫的发病机理与其在复杂生命周期中对基因表达的及时控制息息相关。在这种生物中，基因表达是通过表观遗传机制部分控制的，因此其调控对寄生虫至为重要。恶性疟原虫（Pf）-GCN5组蛋白乙酰转移酶（HAT）是必需酶，乙酰化组蛋白3并调节寄生虫中的整体基因表达。在这里，我们显示了一种新的PfGCN5蛋白水解过程，该过程对其在体内的活性至关重要。我们发现，半胱氨酸蛋白酶样酶是处理PfGCN5蛋白所必需的。免疫荧光和免疫电子显微镜分析表明，加工事件发生在寄生虫通过经典的ER-高尔基体分泌途径运输之后，到达随后的细胞核之前，在消化液的附近。此外，PfGCN5加工的阻断导致其在基因启动子上的占有率随之降低，以及在这些启动子上的H3K9乙酰化水平降低，从而突出了加工事件与PfGCN5活性之间的重要关联。总而言之，我们的研究揭示了核蛋白PfGCN5的独特加工事件，其具有食品液泡半胱氨酸蛋白酶的不可预见的作用。这导致针对这些目标开发新的抗疟药的可能性。