Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
PLoS Pathog. 2024 Sep 6;20(9):e1012484. doi: 10.1371/journal.ppat.1012484. eCollection 2024 Sep.
Glycophosphatidylinositol (GPI) anchors are the predominant glycoconjugate in Plasmodium parasites, enabling modified proteins to associate with biological membranes. GPI biosynthesis commences with donation of a mannose residue held by dolichol-phosphate at the endoplasmic reticulum membrane. In Plasmodium dolichols are derived from isoprenoid precursors synthesised in the Plasmodium apicoplast, a relict plastid organelle of prokaryotic origin. We found that treatment of Plasmodium parasites with apicoplast inhibitors decreases the synthesis of isoprenoid and GPI intermediates resulting in GPI-anchored proteins becoming untethered from their normal membrane association. Even when other isoprenoids were chemically rescued, GPI depletion led to an arrest in schizont stage parasites, which had defects in segmentation and egress. In those daughter parasites (merozoites) that did form, proteins that would normally be GPI-anchored were mislocalised, and when these merozoites were artificially released they were able to attach to but not invade new red blood cells. Our data provides further evidence for the importance of GPI biosynthesis during the asexual cycle of P. falciparum, and indicates that GPI biosynthesis, and by extension egress and invasion, is dependent on isoprenoids synthesised in the apicoplast.
糖基磷脂酰肌醇（GPI）锚定物是疟原虫中主要的糖缀合物，使修饰后的蛋白质能够与生物膜结合。GPI 生物合成始于内质网膜上的多萜醇磷酸末端捐赠一个甘露糖残基。在疟原虫中，多萜醇来源于异戊烯基前体，这些前体在疟原虫的质体中合成，质体是原核起源的遗留质体细胞器。我们发现，用质体抑制剂处理疟原虫会减少异戊烯基和 GPI 中间体的合成，导致 GPI 锚定蛋白与其正常膜结合分离。即使其他异戊烯基被化学挽救，GPI 耗竭也会导致裂殖体阶段寄生虫停滞，这些寄生虫在分裂和逸出时出现缺陷。在形成的那些子寄生虫（裂殖子）中，原本应该是 GPI 锚定的蛋白质发生了定位错误，当这些裂殖子被人为释放时，它们能够附着但不能侵入新的红细胞。我们的数据进一步证明了 GPI 生物合成在疟原虫无性周期中的重要性，并表明 GPI 生物合成以及逸出和入侵，依赖于质体中合成的异戊烯基。
