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.
Highlights
1, 1, Con Dogovski[1], Artemisinin and its derivatives rapidly reduce the parasite burden in Plasmodium falciparum infections, and antimalarial control is highly dependent on ART combination therapies (ACTs)
Consistent with recent reports showing that ARTs induce widespread cellular damage[6,7,8], our data indicate that DHA causes protein damage/unfolding and inhibits folding of newly synthesised proteins
We show that the DHA-initiated proteostatic stress induces eIF2α phosphorylation via activation of PK4, the Plasmodium homologue of mammalian PERK
Summary
1, 1, Con Dogovski[1], 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. DHA is known to cause widespread damage to parasite proteins in different cellular compartments[6,7,8] These damaged proteins would be expected to be targeted for ubiquitination and degradation by the proteasome; and changes that affect this pathway might be expected to help enable parasites to survive DHA exposure. The work reveals new points of vulnerability that could be targeted with chemotherapies against malaria parasites
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