TY - JOUR
T1 - Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome
AU - Bridgford, Jessica L.
AU - Xie, Stanley C.
AU - Cobbold, Simon A.
AU - Pasaje, Charisse Flerida A.
AU - Herrmann, Susann
AU - Yang, Tuo
AU - Gillett, David L.
AU - Dick, Lawrence R.
AU - Ralph, Stuart A.
AU - Dogovski, Con
AU - Spillman, Natalie J.
AU - Tilley, Leann
N1 - Funding Information:
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.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85053450059&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-06221-1
DO - 10.1038/s41467-018-06221-1
M3 - Article
C2 - 30228310
AN - SCOPUS:85053450059
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3801
ER -
