Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome
Published: September 18, 2018
Citation
Artemisinin kills malaria parasites by damaging
proteins and inhibiting the proteasome. Nature Communications, 2018. DOI: 10.1038/s41467-018-06221-1
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 poly-
ubiquitinated 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.