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Proteins associated with ubiquitin-proteasome system (UPS) are potential drug targets in the malaria parasite. The ubiquitination and deubiquitination are key regulatory processes for the functioning of UPS. In this study, we have characterized the biochemical and functional role of a novel ubiquitin-specific protease (USP) domain-containing protein of the human malaria parasite Plasmodium falciparum (PfUSP). We have shown that the PfUSP is an active deubiquitinase associated with parasite endoplasmic reticulum (ER). Selection linked integration (SLI) method for C-terminal tagging and GlmS-ribozyme mediated inducible knock-down (iKD) of PfUSP was utilized to assess its functional role. Inducible knockdown of PfUSP resulted in a remarkable reduction in parasite growth and multiplication; specifically, PfUSP-iKD disrupted ER morphology and development, blocked the development of healthy schizonts, and hindered proper merozoite development. PfUSP-iKD caused increased ubiquitylation of specific proteins, disrupted organelle homeostasis and reduced parasite survival. Since the mode of action of artemisinin and the artemisinin-resistance are shown to be associated with the proteasome machinery, we analyzed the effect of dihydroartemisinin (DHA) on PfUSP-iKD parasites. Importantly, the PfUSP-knocked-down parasite showed increased sensitivity to dihydroartemisinin (DHA), whereas no change in chloroquine sensitivity was observed, suggesting a role of PfUSP in combating artemisinin-induced cellular stress. Together, the results show that Plasmodium PfUSP is an essential protease for parasite survival, and its inhibition increases the efficacy of artemisinin-based drugs. Therefore, PfUSP can be targeted to develop novel scaffolds for developing new antimalarials to combat artemisinin resistance.

Titel:	A Plasmodium falciparum ubiquitin-specific protease (PfUSP) is essential for parasite survival and its disruption enhances artemisinin efficacy.
Autor/in / Beteiligte Person:	Arora, P ; Narwal, M ; Thakur, V ; Mukhtar, O ; Malhotra, P ; Mohmmed, A
Zeitschrift:	The Biochemical journal, Jg. 480 (2023-01-13), Heft 1, S. 25-39
Veröffentlichung:	London, UK : Published by Portland Press on behalf of the Biochemical Society, 2023
Medientyp:	academicJournal
ISSN:	1470-8728 (electronic)
DOI:	10.1042/BCJ20220429
Schlagwort:	Humans Animals Plasmodium falciparum metabolism Proteasome Endopeptidase Complex genetics Proteasome Endopeptidase Complex metabolism Ubiquitin-Specific Proteases metabolism Ubiquitin-Specific Proteases pharmacology Ubiquitin genetics Ubiquitin metabolism Drug Resistance genetics Parasites Artemisinins pharmacology Artemisinins metabolism Antimalarials chemistry Malaria
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Biochem J] 2023 Jan 13; Vol. 480 (1), pp. 25-39. MeSH Terms: Parasites* ; Artemisinins* / pharmacology ; Artemisinins* / metabolism ; Antimalarials* / chemistry ; Malaria* ; Humans ; Animals ; Plasmodium falciparum / metabolism ; Proteasome Endopeptidase Complex / genetics ; Proteasome Endopeptidase Complex / metabolism ; Ubiquitin-Specific Proteases / metabolism ; Ubiquitin-Specific Proteases / pharmacology ; Ubiquitin / genetics ; Ubiquitin / metabolism ; Drug Resistance / genetics Contributed Indexing: Keywords: Plasmodium falciparum; artemisinin resistance; deubiquitinase; malaria; organelle homeostasis Substance Nomenclature: 6A9O50735X (artenimol) ; EC 3.4.25.1 (Proteasome Endopeptidase Complex) ; EC 3.4.19.12 (Ubiquitin-Specific Proteases) ; 0 (Artemisinins) ; 9RMU91N5K2 (artemisinin) ; 0 (Antimalarials) ; 0 (Ubiquitin) Entry Date(s): Date Created: 20221213 Date Completed: 20230110 Latest Revision: 20230216 Update Code: 20240513

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A Plasmodium falciparum ubiquitin-specific protease (PfUSP) is essential for parasite survival and its disruption enhances artemisinin efficacy.