Endoplasmic reticulum (ER) plays a pivotal role in the regulation of stress responses in multiple eukaryotic cells. However, little is known about the effector mechanisms that regulate stress responses in ER of the malaria parasite. Herein, we aimed to identify the importance of a transmembrane protein 33 (TMEM33)-domain-containing protein in life cycle of the rodent malaria parasite Plasmodium berghei. TMEM33 is an ER membrane-resident protein that is involved in regulating stress responses in various eukaryotic cells. A C-terminal tagged TMEM33 was localized in the ER throughout the blood and mosquito stages of development. Targeted deletion of TMEM33 confirmed its importance for asexual blood stages and ookinete development, in addition to its essential role for sporozoite infectivity in the mammalian host. Pilot scale analysis shows that the loss of TMEM33 results in the initiation of ER stress response and induction of autophagy. Our findings conclude an important role of TMEM33 in the development of all life cycle stages of the malaria parasite, which indicates its potential as an antimalarial target.

中文翻译：

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内质网定位的含 TMEM33 结构域的蛋白对于疟疾寄生虫的所有生命周期阶段都至关重要

内质网（ER）在多种真核细胞应激反应的调节中发挥着关键作用。然而，人们对调节疟原虫内质网应激反应的效应机制知之甚少。在此，我们的目的是确定含有跨膜蛋白 33 (TMEM33) 结构域的蛋白质在啮齿动物疟疾寄生虫伯氏疟原虫生命周期中的重要性。 TMEM33 是一种内质网膜驻留蛋白，参与调节各种真核细胞的应激反应。 C 端标记的 TMEM33 在整个血液和蚊子发育阶段都位于内质网中。 TMEM33 的靶向删除证实了其对于无性血液阶段和动合子发育的重要性，以及其在哺乳动物宿主中子孢子感染性中的重要作用。中试规模分析表明，TMEM33 的缺失导致内质网应激反应的启动和自噬的诱导。我们的研究结果得出结论，TMEM33 在疟疾寄生虫所有生命周期阶段的发育中发挥着重要作用，这表明其作为抗疟靶点的潜力。