Review
K13, the Cytostome, and Artemisinin Resistance

https://doi.org/10.1016/j.pt.2020.03.006Get rights and content
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Highlights

  • The cytostome (cell mouth) that the parasite uses to take up hemoglobin is the proposed location for the artemisinin-resistance marker Kelch 13 (K13).

  • K13 mutants exhibit disrupted hemoglobin catabolism.

  • Decreased hemoglobin-dependent activation likely underpins K13-mediated artemisinin resistance.

  • Mutations in other endocytic apparatus proteins may underpin alternative resistance mechanisms.

  • K13 mutations have a fitness cost that may prevent full-blown resistance.

Artemisinins – the frontline antimalarial drug class – are compromised by emerging resistance, putting at risk the lives of hundreds of thousands of people each year. Resistance is associated with mutations in a malaria parasite protein, called Kelch 13 (K13). Recent work suggests that K13 is located at the cytostome (cell mouth) that the parasite uses to take up hemoglobin. Here we explore the proposal that K13 mutations confer artemisinin resistance by dampening hemoglobin endocytosis. This model suggests that the resultant decrease in hemoglobin-derived heme reduces artemisinin activation, which is sufficient to enable parasite survival in the early ring stage of infection. A fuller understanding of the resistance mechanism will underpin efforts to develop alternative antimalarial strategies.

Keywords

artemisinin resistance
Kelch 13
cytostome
hemoglobin uptake
ubiquitination

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