Journal article
Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome
JL Bridgford, SC Xie, SA Cobbold, CFA Pasaje, S Herrmann, T Yang, DL Gillett, LR Dick, SA Ralph, C Dogovski, NJ Spillman, L Tilley
Nature Communications | NATURE PUBLISHING GROUP | Published : 2018
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-me..
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Grants
Awarded by National Health and Medical Research Council
Funding Acknowledgements
We thank Dr Paul Gilson, Prof Brendan Crabb and Dr Mauro F. Azevedo, Burnet Institute, for the DD-GFP parasite line. We thank Christian Doerig, Monash University for providing eIK1 and eIK2 genetically disrupted parasites. We thank Prof Greg Blatch and Eva-Rachele Pesce, Victoria University, for providing recombinant PfBiP. We thank Dr Oded Kleifeld, Technion Israel Institute of Technology and Dr Tobias Spielmann, Bernhard Nocht Institute for Tropical Medicine, for reagents and helpful advice. This work was supported by the National Health & Medical Research Council of Australia and the Australia Research Council.