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:	Noah Machuki Onchieku, Sonam Kumari, Rajan Pandey, Vaibhav Sharma, Mohit Kumar, Arunaditya Deshmukh, Inderjeet Kaur, Asif Mohmmed, Dinesh Gupta, Daniel Kiboi, Naseem Gaur, Pawan Malhotra
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	artemisinin <i>Plasmodium falciparum</i> DNA damage Ddi1 ubiquitin-proteasome pathway enzyme inhibition Medicine R
Acceso en línea:	https://doaj.org/article/12dac69b553b417182b3d7f7b001afec
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spelling	oai:doaj.org-article:12dac69b553b417182b3d7f7b001afec2021-11-25T18:38:28ZArtemisinin Binds and Inhibits the Activity of <i>Plasmodium falciparum</i> Ddi1, a Retroviral Aspartyl Protease10.3390/pathogens101114652076-0817https://doaj.org/article/12dac69b553b417182b3d7f7b001afec2021-11-01T00:00:00Zhttps://www.mdpi.com/2076-0817/10/11/1465https://doaj.org/toc/2076-0817Reduced 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.Noah Machuki OnchiekuSonam KumariRajan PandeyVaibhav SharmaMohit KumarArunaditya DeshmukhInderjeet KaurAsif MohmmedDinesh GuptaDaniel KiboiNaseem GaurPawan MalhotraMDPI AGarticleartemisinin<i>Plasmodium falciparum</i>DNA damageDdi1ubiquitin-proteasome pathwayenzyme inhibitionMedicineRENPathogens, Vol 10, Iss 1465, p 1465 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	artemisinin <i>Plasmodium falciparum</i> DNA damage Ddi1 ubiquitin-proteasome pathway enzyme inhibition Medicine R
spellingShingle	artemisinin <i>Plasmodium falciparum</i> DNA damage Ddi1 ubiquitin-proteasome pathway enzyme inhibition Medicine R Noah Machuki Onchieku Sonam Kumari Rajan Pandey Vaibhav Sharma Mohit Kumar Arunaditya Deshmukh Inderjeet Kaur Asif Mohmmed Dinesh Gupta Daniel Kiboi Naseem Gaur Pawan Malhotra Artemisinin Binds and Inhibits the Activity of <i>Plasmodium falciparum</i> Ddi1, a Retroviral Aspartyl Protease
description	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.
format	article
author	Noah Machuki Onchieku Sonam Kumari Rajan Pandey Vaibhav Sharma Mohit Kumar Arunaditya Deshmukh Inderjeet Kaur Asif Mohmmed Dinesh Gupta Daniel Kiboi Naseem Gaur Pawan Malhotra
author_facet	Noah Machuki Onchieku Sonam Kumari Rajan Pandey Vaibhav Sharma Mohit Kumar Arunaditya Deshmukh Inderjeet Kaur Asif Mohmmed Dinesh Gupta Daniel Kiboi Naseem Gaur Pawan Malhotra
author_sort	Noah Machuki Onchieku
title	Artemisinin Binds and Inhibits the Activity of <i>Plasmodium falciparum</i> Ddi1, a Retroviral Aspartyl Protease
title_short	Artemisinin Binds and Inhibits the Activity of <i>Plasmodium falciparum</i> Ddi1, a Retroviral Aspartyl Protease
title_full	Artemisinin Binds and Inhibits the Activity of <i>Plasmodium falciparum</i> Ddi1, a Retroviral Aspartyl Protease
title_fullStr	Artemisinin Binds and Inhibits the Activity of <i>Plasmodium falciparum</i> Ddi1, a Retroviral Aspartyl Protease
title_full_unstemmed	Artemisinin Binds and Inhibits the Activity of <i>Plasmodium falciparum</i> Ddi1, a Retroviral Aspartyl Protease
title_sort	artemisinin binds and inhibits the activity of <i>plasmodium falciparum</i> ddi1, a retroviral aspartyl protease
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/12dac69b553b417182b3d7f7b001afec
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Artemisinin Binds and Inhibits the Activity of <i>Plasmodium falciparum</i> Ddi1, a Retroviral Aspartyl Protease

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