Plasmodium falciparum GCN5 plays a key role in regulating artemisinin resistance-related stress responses

Abstract

Plasmodium falciparum causes the most severe malaria and is exposed to various environmental and physiological stresses in the human host. Given that GCN5 plays a critical role in regulating stress responses in model organisms, we aimed to elucidate PfGCN5’s function in stress responses in P. falciparum . The protein level of PfGCN5 was substantially induced under three stress conditions [heat shock, low glucose starvation, and dihydroartemisinin, the active metabolite of artemisinin (ART)]. With a TetR-DOZI conditional knockdown (KD) system, we successfully down-regulated PfGCN5 to ~50% and found that KD parasites became more sensitive to all three stress conditions. Transcriptomic analysis via RNA-seq identified ~1,000 up- and down-regulated genes in the wild-type (WT) and KD parasites under these stress conditions. Importantly, DHA induced transcriptional alteration of many genes involved in many aspects of stress responses, which were heavily shared among the altered genes under heat shock and low glucose conditions, including ART-resistance-related genes such as K13 and coronin . Based on the expression pattern between WT and KD parasites under three stress conditions, ~300–400 genes were identified to be involved in PfGCN5-dependent, general, and stress-condition-specific responses with high levels of overlaps among three stress conditions. Notably, using ring-stage survival assay, we found that KD or inhibition of PfGCN5 could sensitize the ART-resistant parasites to the DHA treatment. All these indicate that PfGCN5 is pivotal in regulating general and ART-resistance-related stress responses in malaria parasites, implicating PfGCN5 as a potential target for malaria intervention.

Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum

“…4 ). It has also recently been shown that PfGCN5, a histone acetyl transferase, is involved in the resistance of P. falciparum to artemisinins by increasing the unfold protein response pathway (UPR) and controls 300–400 genes involved in stress responses [ 112 , 113 ]. On this basis, it could be hypothesized that resistance to artemisinins in P. falciparum may also rely on epigenetic regulation.…”

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

“…Blasticidin S resistance is connected with cytoadherence-linked asexual protein 3 (CLAG3), regulated by H3K9ac and H3K9me3 [ 326 ]. Recent studies have demonstrated that PfGCN5 plays a role in artemisinin resistance by enhancing the unfolded protein response (UPR) pathway and regulating 300–400 genes associated with stress responses [ 327 , 328 ]. The inhibition of P.f.…”