PfGCN5, a global regulator of stress responsive genes, modulates artemisinin resistance in Plasmodium falciparum

Abstract

Plasmodium falciparum has evolved resistance to almost all front-line drugs including artemisinins, which threatens malaria control and elimination strategies. Oxidative stress and protein damage responses have emerged as key players in the generation of artemisinin resistance. In this study, we show that PfGCN5, a histone acetyltransferase, binds to the stress responsive and multi-variant family genes in poised state and regulates their expression under stress conditions. We have also provided biochemical and cellular evidences that PfGCN5 regulates stress responsive genes by acetylation of PfAlba3. Furthermore, we show that upon artemisinin exposure, genome-wide binding sites for PfGCN5 are increased and it is directly associated with the genes implicated in artemisinin resistance generation like BiP and TRiC chaperone. Moreover, inhibition of PfGCN5 in artemisinin resistant parasites, Kelch13 mutant, K13I543T and K13C580Y (RSA[~] 25% and 6%, respectively) reverses the sensitivity of the parasites to artemisinin treatment indicating its role in drug resistance generation. Together, these findings elucidate the role of PfGCN5 as a global chromatin regulator of stress-responses with potential role in modulating artemisinin drug resistance, and identify PfGCN5 as an important target against artemisinin resistant parasites.\n\nAuthor SummaryMalaria parasites are constantly adapting to the drugs we used to eliminate them. Thus, when we use the drugs to kill parasites; with time, we select the parasites with the favourable genetic changes. Parasites develop various strategies to overcome exposure to the drugs by exhibiting the stress responses. The changes specific to the drug adapted parasites can be used to understand the mechanism of drug resistance generation. In this study, we have identified PfGCN5 as a global transcriptional regulator of stress responses in Plasmodium falciparum. Inhibition of PfGCN5 reverses the sensitivity of the parasites to the artemisinin drug and identify PfGCN5 as an important target against artemisinin resistant parasites.