Malaria parasites coordinate host cell remodeling through the AP2-HCR DNA-binding protein

Abstract

Parasite-induced host cell remodeling is essential for Plasmodium falciparum survival during the intraerythrocytic developmental cycle (IDC), yet the transcriptional mechanisms coordinating this process remain poorly understood. Here, we characterize an essential ApiAP2 transcription factor, PfAP2-HCR (host cell remodeling), during both the asexual and sexual blood stages of P. falciparum. Conditional truncation of pfap2-hcr demonstrated that PfAP2-HCR is essential for ring stage development and parasite maturation. Loss of PfAP2-HCR disrupted the expression of host cell remodeling genes, resulting in the absence of Maurers clefts and collapse of the parasite protein export machinery. Integrated RNA-seq and ChIP-seq analyses revealed that PfAP2-HCR directly or indirectly regulates approximately 30% of exported proteins, including 27 essential exported factors, the parasitophorous vacuole membrane (PVM) resident protein EXP1, and the core PTEX component EXP2. We further show that PfAP2-HCR is also indispensable for gametocytogenesis, as conditional truncation results in either complete ablation or the formation of severely deformed gametocytes. Together, these findings establish PfAP2-HCR as a central transcriptional regulator that orchestrates the expression of host cell remodeling factors required to transform a terminally differentiated erythrocyte into a permissive environment for parasite survival, development, and transmission.