Emerging resistance to artemisinin (ART) has become a challenge for reducing worldwide malaria mortality and morbidity. The C580Y mutation in Plasmodium falciparum Kelch13 has been identified as the major determinant for ART resistance in the background of other mutations, which include the T38I mutation in autophagy-related protein PfATG18. Increased endoplasmic reticulum phosphatidylinositol-3-phosphate (ER-PI3P) vesiculation, unfolded protein response (UPR), and oxidative stress are the proteostasis mechanisms proposed to cause ART resistance. While UPR and PI3P are known to stimulate autophagy in higher organisms to clear misfolded proteins, participation of the parasite autophagy machinery in these mechanisms of ART resistance has not yet been experimentally demonstrated. Our study establishes that ART-induced ER stress leads to increased expression of P. falciparum autophagy proteins through induction of the UPR. Furthermore, the ART-resistant K13^C580Y isolate shows higher basal expression levels of autophagy proteins than those of its isogenic counterpart, and this magnifies under starvation conditions. The copresence of PfK13 with PfATG18 and PI3P on parasite hemoglobin-trafficking vesicles demonstrate interactions between the autophagy and hemoglobin endocytosis pathways proposed to be involved in ART resistance. Analysis of PfK13 mutations in 2,517 field isolates, revealing an impressive >85% coassociation between PfK13 C580Y and PfATG18 T38I, together with our experimental studies with an ART-resistant P. falciparum strain establishes that parasite autophagy underpins various mechanisms of ART resistance and is a starting point to further explore this pathway for developing antimalarials. IMPORTANCE There is an urgent need to clearly understand the mechanisms of ART resistance as it is emerging in the Greater Mekong Subregion (GMS) and other parts of the world, such as Africa. Deciphering the mechanisms of the parasite's stress response pathways of ART resistance will provide insights to identify novel drug targets for developing new antimalarial regimens.

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