Plasmodium DDI1 is a potential therapeutic target and important chromatin-associated protein.

Autor: Tanneru N; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India., Nivya MA; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India., Adhikari N; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India., Saxena K; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, UP, India., Rizvi Z; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India., Sudhakar R; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India., Nagwani AK; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India., Atul; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India., Mohammed Abdul Al-Nihmi F; Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India., Kumar KA; Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India., Sijwali PS; CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, TS, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, UP, India. Electronic address: psijwali@ccmb.res.in.
Jazyk: angličtina
Zdroj: International journal for parasitology [Int J Parasitol] 2023 Mar; Vol. 53 (3), pp. 157-175. Date of Electronic Publication: 2023 Jan 16.
DOI: 10.1016/j.ijpara.2022.11.007
Abstrakt: 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.
(Copyright © 2023 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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