The Plasmodium falciparum artemisinin resistance-associated protein Kelch 13 is required for formation of normal cytostomes

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Abstract
Artemisinin (ART) is a quick-killing and effective antimalarial activated by the haem derived from haemoglobin digestion. Mutations in the parasite’s Kelch 13 (K13) protein compromise the efficacy of this drug. Recent studies indicate an undefined role for K13 in haemoglobin uptake. Here, we show that K13 is associated with the collar that constricts cytostomal invaginations required for the parasite to ingest host cytosol. Induced mislocalisation of K13 led to the formation of atypical invaginations lacking the cytostomal ring and constricted neck normally associated with cytostomes. Moreover, the levels of haemoglobin degradation products, haem and haemozoin, are decreased when K13 is inactivated. Our findings demonstrate that K13 is required for normal formation and/or stabilisation of the cytostome, and thereby the parasite’s uptake of haemoglobin. This is consistent with perturbation of K13 function leading to decreased activation of ART and consequently, reduced killing. Significance Statement: Artemisinin-resistant parasites contain mutations in the gene encoding the Kelch 13 protein (K13). How K13 mutations result in artemisinin resistance is unclear. Here, we present evidence that normal K13 is required for the formation of the cytostome, a specialised parasite feeding apparatus used to endocytose host cell haemoglobin. Our results suggest that artemisinin resistance is due to a decrease in artemisinin activation brought about by a decrease in efficiency of haemoglobin uptake and consequently reduced production of haem.

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