Journal article
Decreased K13 Abundance Reduces Hemoglobin Catabolism and Proteotoxic Stress, Underpinning Artemisinin Resistance
T Yang, LM Yeoh, MV Tutor, MW Dixon, PJ McMillan, SC Xie, JL Bridgford, DL Gillett, MF Duffy, SA Ralph, MJ McConville, L Tilley, SA Cobbold
Cell Reports | CELL PRESS | Published : 2019
Open access
Abstract
Increased tolerance of Plasmodium falciparum to front-line artemisinin antimalarials (ARTs) is associated with mutations in Kelch13 (K13), although the precise role of K13 remains unclear. Here, we show that K13 mutations result in decreased expression of this protein, while mislocalization of K13 mimics resistance-conferring mutations, pinpointing partial loss of function of K13 as the relevant molecular event. K13-GFP is associated with ∼170 nm diameter doughnut-shaped structures at the parasite periphery, consistent with the location and dimensions of cytostomes. Moreover, the hemoglobin-peptide profile of ring-stage parasites is reduced when K13 is mislocalized. We developed a pulse-SILA..
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Funding Acknowledgements
We thank the Mass Spectrometry and Proteomics facility, Bio21 Institute, for mass spectrometry support and the Biological Optical Microscopy Platform. We thank the Australian Red Cross service for blood donations. We thank Prof. Paul Horrocks, Keele University, for plasmid reagents and Dr. Tobias Spielmann and Dr. Jakob Birnbaum, Bernhard Nocht Institute for Tropical Medicine, for GFP-2xFKBP-K13<SUP>WT</SUP> parasites. Moreover, We appreciate the thoughtful discussions and input from Dr. Heather Painter and Dr. Natalie Spillman. This work was supported by the National Health & Medical Research Council of Australia (NHMRC) and the Australian Research Council (ARC).