UIS2: A Unique Phosphatase Required for the Development of Plasmodium Liver Stages.
UIS2: A Unique Phosphatase Required for the Development of Plasmodium Liver Stages.
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DOI：
10.1371/journal.ppat.1005370
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发表时间：
2016-01
期刊：
影响因子：
6.7
通讯作者：
Nussenzweig V
中科院分区：
文献类型：
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作者：
Zhang M;Mishra S;Sakthivel R;Fontoura BM;Nussenzweig V
疟原虫唾液子孢子是疟疾寄生虫的感染形式，并且在按蚊的唾液腺内休眠。在休眠期间，蛋白质翻译受到激酶UIS 1的抑制，该激酶UIS 1磷酸化真核起始因子2α（eIF 2 α）中的丝氨酸59。eIF 2 α-P的去磷酸化是子孢子转化为肝阶段所必需的。在哺乳动物细胞中，eIF 2 α-P的去磷酸化是由蛋白磷酸酶1（PP 1）介导的。使用一系列基因敲除的寄生虫，我们发现在疟疾子孢子中，与哺乳动物细胞相反，eIF 2 α-P磷酸酶是PP 2C/PPM磷酸酶家族的成员，称为UIS 2。我们发现eIF 2 α在uis 2条件敲除子孢子中高度磷酸化。这些突变子孢子进入哺乳动物宿主后仍保持新月形，丧失了感染性。uis 1和uis 2都在唾液腺子孢子中高度转录，但uis 2的表达被Pumilio蛋白Puf 2抑制。当子孢子发育到肝期时，uis 2表达的抑制减轻。虽然大多数真核生物的磷酸酶与它们的底物瞬时相互作用，但UIS 2稳定地结合磷酸化的eIF 2 α，提高了高通量搜索可能识别破坏这种相互作用并预防疟疾感染的化学物质的可能性。疟疾是通过雌蚊吸血传播给人类的。疟原虫子孢子是寄生在蚊子唾液腺中的疟原虫的感染性和静止形式。通过翻译因子eIF 2 α的磷酸化抑制子孢子中的整体蛋白质合成。然而，寄生虫在宿主肝脏中的发展需要eIF 2 α-P的去磷酸化。我们发现，一种独特的疟原虫磷酸酶UIS 2在疟疾中使eIF 2 α-P去磷酸化。eIF 2 α在uis 2突变子孢子中高度磷酸化。uis 2突变体寄生虫在进入宿主后没有改变它们的形态，并且不能正确地感染宿主。我们还发现UIS 2的表达受到Pumilio蛋白Puf 2的抑制。但当子孢子发育到肝期时，这种抑制作用被解除。总之，我们的研究结果揭示了一种新的机制，进化控制eIF 2 α去磷酸化，并表明UIS 2抑制剂的鉴定可能有助于抗疟疾治疗。
Plasmodium salivary sporozoites are the infectious form of the malaria parasite and are dormant inside salivary glands of Anopheles mosquitoes. During dormancy, protein translation is inhibited by the kinase UIS1 that phosphorylates serine 59 in the eukaryotic initiation factor 2α (eIF2α). De-phosphorylation of eIF2α-P is required for the transformation of sporozoites into the liver stage. In mammalian cells, the de-phosphorylation of eIF2α-P is mediated by the protein phosphatase 1 (PP1). Using a series of genetically knockout parasites we showed that in malaria sporozoites, contrary to mammalian cells, the eIF2α-P phosphatase is a member of the PP2C/PPM phosphatase family termed UIS2. We found that eIF2α was highly phosphorylated in uis2 conditional knockout sporozoites. These mutant sporozoites maintained the crescent shape after delivery into mammalian host and lost their infectivity. Both uis1 and uis2 were highly transcribed in the salivary gland sporozoites but uis2 expression was inhibited by the Pumilio protein Puf2. The repression of uis2 expression was alleviated when sporozoites developed into liver stage. While most eukaryotic phosphatases interact transiently with their substrates, UIS2 stably bound to phosphorylated eIF2α, raising the possibility that high-throughput searches may identify chemicals that disrupt this interaction and prevent malaria infection. Malaria is transmitted to humans by female mosquitoes as they take a blood meal. Plasmodium sporozoites are the infectious and quiescent forms of malaria parasites, which reside in the salivary glands of mosquitoes. Global protein synthesis is inhibited in sporozoites through phosphorylation of the translational factor eIF2α. However, the development of the parasites in the host liver requires de-phosphorylation of eIF2α-P. We find that a unique Plasmodium phosphatase termed UIS2 de-phosphorylates eIF2α-P in malaria. The eIF2α is highly phosphorylated in the uis2 mutant sporozoites. The uis2 mutant parasites did not change their morphology after delivery into the host and could not properly infect the host. We also showed that UIS2 expression was inhibited by the Pumilio protein Puf2. However, this repression was relieved when sporozoites developed into liver stage. In sum, our findings revealed a new mechanism that evolved to control eIF2α dephosphorylation and suggest that identification of UIS2 inhibitors may be useful in anti-malaria therapy.