Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome

Jessica L. Bridgford, Stanley C. Xie, Simon A. Cobbold, Charisse Flerida A. Pasaje, Susann Herrmann, Tuo Yang, David L. Gillett, Lawrence R. Dick, Stuart A. Ralph, Con Dogovski, Natalie J. Spillman and Leann Tilley ()
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Jessica L. Bridgford: The University of Melbourne
Stanley C. Xie: The University of Melbourne
Simon A. Cobbold: The University of Melbourne
Charisse Flerida A. Pasaje: The University of Melbourne
Susann Herrmann: The University of Melbourne
Tuo Yang: The University of Melbourne
David L. Gillett: The University of Melbourne
Lawrence R. Dick: Takeda Pharmaceuticals International Co
Stuart A. Ralph: The University of Melbourne
Con Dogovski: The University of Melbourne
Natalie J. Spillman: The University of Melbourne
Leann Tilley: The University of Melbourne

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06221-1

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