Artemisinin Binds and Inhibits the Activity of <i>Plasmodium falciparum</i> Ddi1, a Retroviral Aspartyl Protease
Reduced sensitivity of the human malaria parasite, <i>Plasmodium falciparum,</i> to Artemisinin and its derivatives (ARTs) threatens the global efforts towards eliminating malaria. ARTs have been shown to cause ubiquitous cellular and genetic insults, which results in the activation of t...
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| Autores principales: | , , , , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/12dac69b553b417182b3d7f7b001afec |
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| Sumario: | Reduced sensitivity of the human malaria parasite, <i>Plasmodium falciparum,</i> to Artemisinin and its derivatives (ARTs) threatens the global efforts towards eliminating malaria. ARTs have been shown to cause ubiquitous cellular and genetic insults, which results in the activation of the unfolded protein response (UPR) pathways. The UPR restores protein homeostasis, which otherwise would be toxic to cellular survival. Here, we interrogated the role of DNA-damage inducible protein 1 (<i>Pf</i>Ddi1), a unique proteasome-interacting retropepsin in mediating the actions of the ARTs. We demonstrate that <i>Pf</i>Ddi1 is an active A<sub>2</sub> family protease that hydrolyzes ubiquitinated proteasome substrates. Treatment of <i>P. falciparum</i> parasites with ARTs leads to the accumulation of ubiquitinated proteins in the parasites and blocks the destruction of ubiquitinated proteins by inhibiting the <i>Pf</i>Ddi1 protease activity. Besides, whereas the <i>Pf</i>Ddi1 is predominantly localized in the cytoplasm, exposure of the parasites to ARTs leads to DNA fragmentation and increased recruitment of the <i>Pf</i>Ddi1 into the nucleus. Furthermore, we show that Ddi1 knock-out <i>Saccharomyces</i><i>cerevisiae</i> cells are more susceptible to ARTs and the <i>Pf</i>DdI1 protein robustly restores the corresponding functions in the knock-out cells. Together, these results show that ARTs act in multiple ways; by inducing DNA and protein damage and might be impairing the damage recovery by inhibiting the activity of <i>Pf</i>Ddi1, an essential ubiquitin-proteasome retropepsin. |
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