A Plasmodium falciparum molecular mechanism of heme binding and sensitivity to artemisinins
Dutta, S.; Faaiz, M.; Bhattacharjee, S.; Haldar, K.; Bhattacharjee, S.
Show abstract
Mutations in Plasmodium falciparum Kelch13 (K13) confer artemisinin resistance (ART-R) which threatens global malaria control, but known K13 functions fail to explain clinical ART-R. We reported that K13 binds the oxidant heme in vitro, however, its functions in redox-stress, cell survival and death remained unknown. Since taut control of free heme is not feasible in infected erythrocytes, we utilized a non-erythroid cell model to show that K13 directly binds and is stabilized by nanomolar heme levels. K13 also binds and regulates a major redox transcription factor, which is displaced by heme into the nucleus, to raise redox-stress responses that become suppressed during artemisinin-induced death (ART-death). K13s evolutionarily conserved kelch domain confers heme-binding and ART-death characteristics to its mammalian orthologue KEAP1. Chemical or genetic elevation of K13, fuels ART-death proportionate to K13 levels even in vast excess of heme, suggesting a novel plasmodial redox-survival mechanism licenses ART-death in clinical ART-R.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Amino acid restriction sensitizes lung cancer cells toferroptosis via GCN2-dependent activation of the integratedstress response 96%
- PRPS activity tunes redox homeostasis in Myc-driven lymphoma 95%
- The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness 94%
Similar papers in this journal
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.