Abstract:
:Artemisinin and its derivatives (collectively referred to as ARTs) rapidly reduce the parasite burden in Plasmodium falciparum infections, and antimalarial control is highly dependent on ART combination therapies (ACTs). Decreased sensitivity to ARTs is emerging, making it critically important to understand the mechanism of action of ARTs. Here we demonstrate that dihydroartemisinin (DHA), the clinically relevant ART, kills parasites via a two-pronged mechanism, causing protein damage, and compromising parasite proteasome function. The consequent accumulation of proteasome substrates, i.e., unfolded/damaged and polyubiquitinated proteins, activates the ER stress response and underpins DHA-mediated killing. Specific inhibitors of the proteasome cause a similar build-up of polyubiquitinated proteins, leading to parasite killing. Blocking protein synthesis with a translation inhibitor or inhibiting the ubiquitin-activating enzyme, E1, reduces the level of damaged, polyubiquitinated proteins, alleviates the stress response, and dramatically antagonizes DHA activity.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Bridgford JL,Xie SC,Cobbold SA,Pasaje CFA,Herrmann S,Yang T,Gillett DL,Dick LR,Ralph SA,Dogovski C,Spillman NJ,Tilley Ldoi
10.1038/s41467-018-06221-1subject
Has Abstractpub_date
2018-09-18 00:00:00pages
3801issue
1issn
2041-1723pii
10.1038/s41467-018-06221-1journal_volume
9pub_type
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