DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages

Abstract

Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the molecular regulation is poorly understood. Here we have characterized an essential Plasmodium-specific Apicomplexan AP2 transcription factor in Plasmodium falciparum (PfAP2-P; pathogenesis) during the blood-stage development with two peaks of expression. An inducible knockout of gene function showed that PfAP2-P is essential for trophozoite development, and critical for var gene regulation, merozoite development and parasite egress. Chromatin immunoprecipitation sequencing data collected at timepoints matching the two peaks of pfap2-p expression demonstrate PfAP2-P binding to promoters of genes controlling trophozoite development, host cell remodelling, antigenic variation and pathogenicity. Single-cell RNA sequencing and fluorescence-activated cell sorting revealed de-repression of most var genes in Δpfap2-p parasites. Δpfap2-p parasites also overexpress early gametocyte marker genes, indicating a regulatory role in sexual stage conversion. We conclude that PfAP2-P is an essential upstream transcriptional regulator at two distinct stages of the intra-erythrocytic development cycle.

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

“…Twenty-seven Apicomplexan-specific AP2 (ApiAP2) DNA-binding proteins have been identified in Plasmodium falciparum and they are the main factors regulating transcription. Although they are not as numerous as in other eukaryotic organisms with comparable genome sizes, such as yeast, their function is essential to the parasite's life cycle and its ability to adapt to changes in its environment [ 27 – 30 ]. PfAP2-P is involved in the regulation of gene expression during parasite development growth and pathogenesis [ 30 ] and PfAP2-G in the switch from asexual to gametocytes [ 31 , 32 ].…”

“…Although they are not as numerous as in other eukaryotic organisms with comparable genome sizes, such as yeast, their function is essential to the parasite's life cycle and its ability to adapt to changes in its environment [ 27 – 30 ]. PfAP2-P is involved in the regulation of gene expression during parasite development growth and pathogenesis [ 30 ] and PfAP2-G in the switch from asexual to gametocytes [ 31 , 32 ]. Thus, in Plasmodium, epigenetic regulations could represent a main form of regulation of gene expression close to those in ancestral eukaryotic groups [ 33 ] at each step of the parasite life cycle, either at the intra-mosquito, hepatic or intraerythrocytic stage [ 34 – 37 ].…”

Plasmodium falciparumSET10 is a histone H3 lysine K18 methyltransferase that participates in a chromatin modulation network crucial for intraerythrocytic development

“…40), and the var gene promotor-associated chromatin remodeling protein PfISWI (hit no. 43, see Table S6), for which protein interactomics data are available (Bryant et al, 2020;Chahine et al, 2023;Subudhi et al, 2023;Singh et al, 2024). We thus compared the interactors of PfAP2-P, PfISWI, PfMORC, and PfSET10, and identified a total of 328 proteins, with which at least two of the bait proteins interacted (Fig.…”

Plasmodial Transcription Factors and Chromatin Modifiers as Drug Targets

“…Recently, another AP2 factor -PfAP2-P -was found to be essential during the blood stage. The factor apparently controlled a vast number of transcripts important not only for egress/invasion, but also transcripts from variant family genes and gametocyte developmental markers [112], indicating a very important general role for this factor, at least in P. falciparum. Surely, inhibitors of PfAP2-P would probably have an immediate and huge impact on parasite proliferation, warranting further research on this factor.…”