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Abstract：
Remodeling the erythrocyte membrane and skeleton by the malarial parasite Plasmodium falciparum is closely associated with intraerythrocytic development. However, the mechanisms underlying this association remain unclear. In this study, we present evidence that erythrocytic α-spectrin, but not β-spectrin, was dynamically ubiquitinated and progressively degraded during the intraerythrocytic development of P. falciparum, from the ring to the schizont stage. We further observed an upregulated expression of P. falciparum phosphatidylinositol 3-kinase (PfPI3K) in the infected red blood cells during the intraerythrocytic development of the parasite. The data indicated that PfPI3K phosphorylated and activated erythrocytic ubiquitin-protein ligase, leading to increased α-spectrin ubiquitination and degradation during P. falciparum development. We further revealed that inhibition of the activity of PfPI3K impaired P. falciparum development in vitro and Plasmodium berghei infectivity in mice. These findings collectively unveil an important mechanism of PfPI3K-ubiquitin-mediated degradation of α-spectrin during the intraerythrocytic development of Plasmodium species. Proteins in the PfPI3K regulatory pathway are novel targets for effective treatment of severe malaria.
OBJECTIVE: Plasmodium falciparum is the causative agent of severe malaria that causes millions of deaths globally. The parasite invades human red blood cells and induces a cascade of alterations in erythrocytes for development and proliferation. Remodeling the host erythrocytic cytoskeleton is a necessary process during parasitization, but its regulatory mechanisms remain to be elucidated. In this study, we observed that erythrocytic α-spectrin is selectively degraded after P. falciparum invasion, while β-spectrin remained intact. We found that the α-spectrin chain was profoundly ubiquitinated by E3 ubiquitin ligase and degraded by the 26S proteasome. E3 ubiquitin ligase activity was regulated by P. falciparum phosphatidylinositol 3-kinase (PfPI3K) signaling. Additionally, blocking the PfPI3K-ubiquitin-proteasome pathway in P. falciparum-infected red blood cells reduced parasite proliferation and infectivity. This study deepens our understanding of the regulatory mechanisms of host and malarial parasite interactions and paves the way for the exploration of novel antimalarial drugs.
OBJECTIVE: Plasmodium falciparum is the causative agent of severe malaria that causes millions of deaths globally. The parasite invades human red blood cells and induces a cascade of alterations in erythrocytes for development and proliferation. Remodeling the host erythrocytic cytoskeleton is a necessary process during parasitization, but its regulatory mechanisms remain to be elucidated. In this study, we observed that erythrocytic α-spectrin is selectively degraded after P. falciparum invasion, while β-spectrin remained intact. We found that the α-spectrin chain was profoundly ubiquitinated by E3 ubiquitin ligase and degraded by the 26S proteasome. E3 ubiquitin ligase activity was regulated by P. falciparum phosphatidylinositol 3-kinase (PfPI3K) signaling. Additionally, blocking the PfPI3K-ubiquitin-proteasome pathway in P. falciparum-infected red blood cells reduced parasite proliferation and infectivity. This study deepens our understanding of the regulatory mechanisms of host and malarial parasite interactions and paves the way for the exploration of novel antimalarial drugs.
摘要：
疟疾寄生虫恶性疟原虫重塑红细胞膜和骨骼与红细胞内发育密切相关。然而,这种关联的潜在机制仍不清楚.在这项研究中,我们提供的证据表明红细胞α-血影蛋白，但不是β-光谱蛋白，在恶性疟原虫的红细胞内发育过程中动态泛素化并逐渐降解，从戒指到分裂阶段。我们进一步观察到在寄生虫的红细胞内发育过程中，感染的红细胞中恶性疟原虫磷脂酰肌醇3激酶（PfPI3K）的表达上调。数据表明，PfPI3K磷酸化和活化的红细胞泛素蛋白连接酶，导致恶性疟原虫发育过程中α-血影蛋白泛素化和降解增加。我们进一步揭示了抑制PfPI3K的活性会损害恶性疟原虫的体外发育和小鼠中的伯氏疟原虫感染性。这些发现共同揭示了疟原虫物种红细胞内发育过程中PfPI3K-泛素介导的α-血影蛋白降解的重要机制。PfPI3K调节途径中的蛋白质是有效治疗重症疟疾的新靶标。
目的：恶性疟原虫是导致全球数百万人死亡的严重疟疾的病原体。寄生虫侵入人类红细胞并诱导红细胞的级联变化以促进发育和增殖。重塑宿主红细胞细胞骨架是寄生过程中的必要过程，但其监管机制仍有待阐明。在这项研究中,我们观察到红细胞α-血影蛋白在恶性疟原虫入侵后选择性降解，而β-血影蛋白保持完整。我们发现α-血影蛋白链被E3泛素连接酶深深地泛素化，并被26S蛋白酶体降解。E3泛素连接酶活性受恶性疟原虫磷脂酰肌醇3-激酶(PfPI3K)信号调节。此外,在恶性疟原虫感染的红细胞中阻断PfPI3K-泛素-蛋白酶体途径降低了寄生虫的增殖和感染性。这项研究加深了我们对宿主和疟疾寄生虫相互作用的调节机制的理解，并为探索新型抗疟药物铺平了道路。
目的：恶性疟原虫是导致全球数百万人死亡的严重疟疾的病原体。寄生虫侵入人类红细胞并诱导红细胞的级联变化以促进发育和增殖。重塑宿主红细胞细胞骨架是寄生过程中的必要过程，但其监管机制仍有待阐明。在这项研究中,我们观察到红细胞α-血影蛋白在恶性疟原虫入侵后选择性降解，而β-血影蛋白保持完整。我们发现α-血影蛋白链被E3泛素连接酶深深地泛素化，并被26S蛋白酶体降解。E3泛素连接酶活性受恶性疟原虫磷脂酰肌醇3-激酶(PfPI3K)信号调节。此外,在恶性疟原虫感染的红细胞中阻断PfPI3K-泛素-蛋白酶体途径降低了寄生虫的增殖和感染性。这项研究加深了我们对宿主和疟疾寄生虫相互作用的调节机制的理解，并为探索新型抗疟药物铺平了道路。
