Editors' ChoiceParasitology

Antimalarial drugs inhibit PI3P production

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Sci. Signal.  05 May 2015:
Vol. 8, Issue 375, pp. ec118
DOI: 10.1126/scisignal.aac4781

Artemisinins are antimalarial drugs that disrupt the parasite Plasmodium falciparum at multiple stages in the parasite's life cycle, but resistance to these drugs is rising. GWAS (genome-wide association studies) had identified mutations in the P. falciparum gene that encodes PfKelch13, a homolog of a mammalian adaptor for an E3 ubiquitin ligase, as important for artemisinin resistance. Mbenque et al. found that mutation of PfKelch13 confers resistance to artemisinins by increasing the stability of the enzyme in the parasite that produces the signaling lipid phosphatidylinositol-3-phosphate (PI3P). PI3P is a lipid that is important for exporting proteins that mediate virulence from this intracellular parasite into red blood cells. When added to cultures of P. falciparum–infected human erythrocytes, dihydroartemisinin (DHA), the active metabolite of artemisinin-based drugs, inhibited P. falciparum phosphatidylinositol 3-kinase (PfPI3K), the enzyme that produces PI3P. The abundance of PfPI3K and PI3P was increased in strains of P. falciparum carrying a common resistance-associated mutant form of PfKelch13 (PfKelchC580Y). Whereas wild-type PfKelch13 (PfKelch13WT) coimmunoprecipiated with PfPI3K from parasite extracts, little PfKelch13C580Y coimmunoprecipitated with PfPI3K. PfPI3K that was bound to PfKelch13WT contained polyubiquitination modifications and was fragmented in a manner consistent with proteasomal degradation. In contrast, PfPI3K that was bound to PfKelch13C580Y showed reduced polyubiqutination and less fragmentation. Increased abundance of PI3P positively correlated with artemisinin resistance in several clinical and laboratory strains of P. falciparum. Furthermore, experimentally increasing PI3P production in the absence of PfKelch13 mutation conferred resistance to artemisinin. This mechanism of resistance appears to be specific for early stages of infection, when the parasite adopts a ring-shaped form inside red blood cells, implying that other mechanisms mediate DHA action and resistance to DHA at later stages of the parasite's life cycle (see commentary by Burrows).

A. Mbengue, S. Bhattacharjee, T. Pandharkar, H. Liu, G. Estiu, R. V. Stahelin, S. S. Rizk, D. L. Njimoh, Y. Ryan, K. Chotivanich, C. Nguon, M. Ghorbal, J. -J. Lopez-Rubio, M. Pfrender, S. Emrich, N. Mohandas, A. M. Dondorp, O. Wiest, K. Haldar, A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature 520, 683–687 (2015). [PubMed]

J. Burrows, Malaria runs rings round artemisinin. Nature 520, 628–630 (2015). [PubMed]