Tanneru Nandita, Nivya M Angel, Adhikari Navin, Saxena Kanika, Rizvi Zeba, Sudhakar Renu, Nagwani Amit Kumar, Mohammed Abdul Al-Nihmi Faisal, Kumar Kota Arun, Sijwali Puran Singh
CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India.
CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, UP, India.
Int J Parasitol. 2023 Mar;53(3):157-175. doi: 10.1016/j.ijpara.2022.11.007. Epub 2023 Jan 16.
DNA damage inducible 1 protein (DDI1) is involved in a variety of cellular processes including proteasomal degradation of specific proteins. All DDI1 proteins contain a ubiquitin-like (UBL) domain and a retroviral protease (RVP) domain. Some DDI1 proteins also contain a ubiquitin-associated (UBA) domain. The three domains confer distinct activities to DDI1 proteins. The presence of a RVP domain makes DDI1 a potential target of HIV protease inhibitors, which also block the development of malaria parasites. Hence, we investigated the DDI1 of malaria parasites to identify its roles during parasite development and potential as a therapeutic target. DDI1 proteins of Plasmodium and other apicomplexan parasites share the UBL-RVP domain architecture, and some also contain the UBA domain. Plasmodium DDI1 is expressed across all the major life cycle stages and is important for parasite survival, as conditional depletion of DDI1 protein in the mouse malaria parasite Plasmodium berghei and the human malaria parasite Plasmodium falciparum compromised parasite development. Infection of mice with DDI1 knock-down P. berghei was self-limiting and protected the recovered mice from subsequent infection with homologous as well as heterologous parasites, indicating the potential of DDI1 knock-down parasites as a whole organism vaccine. Plasmodium falciparum DDI1 (PfDDI1) is associated with chromatin and DNA-protein crosslinks. PfDDI1-depleted parasites accumulated DNA-protein crosslinks and showed enhanced susceptibility to DNA-damaging chemicals, indicating a role of PfDDI1 in removal of DNA-protein crosslinks. Knock-down of PfDDI1 increased susceptibility to the retroviral protease inhibitor lopinavir and antimalarial artemisinin, which suggests that simultaneous inhibition of DDI1 could potentiate antimalarial activity of these drugs. As DDI1 knock-down parasites confer protective immunity and it could be a target of HIV protease inhibitors, Plasmodium DDI1 is a potential therapeutic target for malaria control.
DNA损伤诱导蛋白1（DDI1）参与多种细胞过程，包括特定蛋白质的蛋白酶体降解。所有DDI1蛋白都包含一个类泛素（UBL）结构域和一个逆转录病毒蛋白酶（RVP）结构域。一些DDI1蛋白还包含一个泛素相关（UBA）结构域。这三个结构域赋予DDI1蛋白不同的活性。RVP结构域的存在使DDI1成为HIV蛋白酶抑制剂的潜在靶点，而HIV蛋白酶抑制剂也会阻碍疟原虫的发育。因此，我们研究了疟原虫的DDI1，以确定其在寄生虫发育过程中的作用以及作为治疗靶点的潜力。疟原虫和其他顶复门寄生虫的DDI1蛋白具有UBL-RVP结构域架构，有些还包含UBA结构域。疟原虫DDI1在所有主要生命周期阶段均有表达，对寄生虫存活至关重要，因为在小鼠疟原虫伯氏疟原虫和人类疟原虫恶性疟原虫中条件性耗尽DDI1蛋白会损害寄生虫发育。用DDI1敲低的伯氏疟原虫感染小鼠具有自限性，并能保护恢复后的小鼠免受同源和异源寄生虫的后续感染，这表明敲低DDI1的寄生虫作为全生物体疫苗的潜力。恶性疟原虫DDI1（PfDDI1）与染色质和DNA-蛋白质交联有关。PfDDI1耗尽的寄生虫积累了DNA-蛋白质交联，并对DNA损伤化学物质表现出增强的敏感性，这表明PfDDI1在去除DNA-蛋白质交联中起作用。敲低PfDDI1会增加对逆转录病毒蛋白酶抑制剂洛匹那韦和抗疟药物青蒿素的敏感性，这表明同时抑制DDI1可以增强这些药物的抗疟活性。由于敲低DDI1的寄生虫具有保护性免疫，并且它可能是HIV蛋白酶抑制剂的靶点，疟原虫DDI1是控制疟疾的潜在治疗靶点。
