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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum
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Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum

机译：基因破坏证实半胱氨酸蛋白酶falcipain-2在恶性疟原虫的血红蛋白水解中起关键作用

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摘要

Erythrocytic malaria parasites degrade hemoglobin in an acidic food vacuole to acquire free amino acids and maintain parasite homeostasis. Hemoglobin hydrolysis appears to be a cooperative process requiring cysteine proteases (falcipains) and aspartic proteases (plasmepsins), but the specific roles of different enzymes in this process are unknown. We previously showed that falcipain-2 is a major trophozoite food vacuole cysteine protease. To characterize the specific role of falcipain-2, we disrupted the falcipain-2 gene and assessed the effect of this alteration. Falcipain-2-knockout trophozoites had markedly diminished cysteine protease activity and swollen, dark staining food vacuoles, consistent with a block in hemoglobin hydrolysis, as caused by cysteine protease inhibitors. However, more mature stages of knockout parasites were indistinguishable from wild-type parasites and developed normally. The knockout parasites had decreased and delayed expression of falcipain-2, which appeared to be directed by increased transcription of a second copy of the gene (falcipain-2'). Expression of other falcipains and plasmelpsins was similar in wild-type and knockout parasites. Compared with wild-type, knockout parasites were about 3 times more sensitive to the cysteine protease inhibitors E-64 and leupeptin, and over 50-fold more sensitive to the aspartic protease inhibitor pepstatin. Our results assign a specific function for falcipain-2, the hydrolysis of hemoglobin in trophozoites. In addition, they highlight the cooperative action of cysteine and aspartic proteases in hemoglobin degradation by malaria parasites. [References: 37]
机译：红细胞疟原虫可降解酸性食物液泡中的血红蛋白，以获取游离氨基酸并维持寄生虫体内稳态。血红蛋白水解似乎是一个需要半胱氨酸蛋白酶（falcipains）和天冬氨酸蛋白酶（plasmepsins）的协同过程，但在此过程中不同酶的具体作用尚不清楚。我们先前显示，falcipain-2是主要的滋养体食物液泡半胱氨酸蛋白酶。为了表征falcipain-2的特定作用，我们破坏了falcipain-2基因并评估了这种改变的效果。 Falcipain-2-knockout滋养体显着降低了半胱氨酸蛋白酶的活性，使食物的肿胀变暗，呈深色，与半胱氨酸蛋白酶抑制剂引起的血红蛋白水解受阻一致。但是，敲除寄生虫的更成熟阶段与野生型寄生虫没有区别，并且发育正常。敲除寄生虫减少并延迟了falcipain-2的表达，这似乎是由该基因第二个拷贝（falcipain-2'）的转录增加所指导的。在野生型和基因敲除寄生虫中，其他falcipains和plasmelpsins的表达相似。与野生型相比，敲除寄生虫对半胱氨酸蛋白酶抑制剂E-64和亮肽素的敏感性高约3倍，对天冬氨酸蛋白酶抑制剂胃抑素的敏感性高50倍以上。我们的结果为falcipain-2（滋养体中血红蛋白的水解）分配了特定功能。此外，它们突出了半胱氨酸和天冬氨酸蛋白酶在疟原虫对血红蛋白降解中的协同作用。 [参考：37]

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