Emerging resistance to artemisinin (ART) has become a challenge for reducing worldwide malaria mortality and morbidity. Increased endoplasmic reticulum phosphatidylinositol-3-phosphate (ER-PI3P) vesiculation, UPR, and oxidative stress are the proteostasis mechanisms proposed to cause ART resistance. Our major efforts are focused on understanding the molecular mechanisms underlying these proteostasis pathways underlying ART resistance. Towards this, we are investigating in detail the various stress response pathways including parasite autophagy and UPR using biochemical, cell biology and molecular biology approaches by using ART resistant parasite cell lines.
Our studies reveal that parasite autophagy mediates various proteostasis mechanisms of ART resistance. We also study regulation of various mechanisms in ART resistance and non-canonical, canonical role of autophagy proteins in P. falciparum.
Schematic representation for role of autophagy in proteostasis mechanisms of ART resistance in P. falciparum. Activated ART generates reactive oxygen species (ROS) and leads to alkylation and misfolding of proteins, causing activation of the stress response pathways. The major source of amino acid supply, host hemoglobin endocytosis, is diminished at the ring stage in PfK13 mutants, reducing ART activation and decreasing protein misfolding. The reduced hemoglobin uptake in PfK13 mutants results in limited nutrient conditions that induces autophagy. Also, the decrease in PI3K ubiquitination and degradation leads to increased PI3P vesiculation, which induces the parasite autophagy pathway. Our results reveal that PfK13 mutants have increased levels of autophagy proteins, indicating the role of autophagy in the survival of the resistant parasites.
© 2021, JNCASR, Jakkur, Bangalore, India