Fig. 2

Mechanism proposed for PfK13-mediated resistance to artemisinins in K13 mutated Plasmodium falciparum at young ring stage. K13-propeller mutation prevents the fixation of uTF and PI3K to the Kelch domain and their ubiquitination, leading to enhanced concentration of PI3P. The artemisinin-induced oxidative stress is responsible for the accumulation of misfolded proteins in the ER endoplasmic reticulum. Misfolded proteins bind to BiP, the complex BiP-PfPK4 is dissociated and PfPK4 phosphorylates uTF and elF2α. elF2α phosphorylation should allow the translocation of uTF in the nucleus to regulate UPR targets and cytoprotective gene expression and also inhibit protein synthesis [75]. BiP immunoglobulin-binding protein, BTB broad-complex, tramtrack and Bric a Brac, CYPB cyclophilin B, eIF2α eukaryotic translation initiation factor 2α, ERC endoplasmic reticulum resident calcium binding protein, PfPK4 P. falciparum protein kinase 4, PI3K phosphatidylinositol 3 kinase, PI3P phosphatidylinositol 3 phosphate, uTF unidentified transcription factor(s)