Prefoldins are novel regulators of molecular mechanism associated with unfolded protein response in artemisinin resistant P. falciparum malaria

Abstract

Abstract Emerging Artemisinin (ART) resistance in Plasmodium demands novel drugs that can target artemisinin resistance mechanism to manage resistant parasites. ART resistance is attributed by mutations in the Plasmodium falciparum (Pf) Kelch-13 (PfK13) gene, however a study showed that artemisinin resistance is linked with up-regulated expression of unfolded protein response pathways involving Prefoldins (PFD) of malaria parasite. Here, we functionally characterized all Pf Prefoldin subunits, the causative links responsible for providing artemisinin resistance. PfPFD-6 interacts with PfK13 and this phenotype was confirmed in yeast orthologous system to show that Prefoldin decrease the sensitivity of artemisinin in mutant strains. Expression of Prefoldin subunits was upregulated in artemisinin resistant line Pfk13R539T, underscoring their significance in providing artemisinin resistance. PfPFD1-6 localize in the cytosol, and these subunits interact in an orchestrated manner (-PFD3-PFD2-PFD1-PFD5-PFD6-PFD4-) to form a jelly-fish like complex. We identified an FDA approved drug ‘Biperiden’ that restricts the formation of Prefoldin complex and inhibits its interaction with key parasite proteins, MSP-1 and α-tubulin-I. Moreover, Biperiden treatment inhibits the parasite growth in Pf3D7 artimisinin sensitive and resistant line. Overall, our study provides novel virtues towards understanding the role of PfPFDs in artemisinin resistance mechanism, and opens new avenues for the management of resistant parasite.