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

Parasite-induced host cell remodeling is essential for Plasmodium falciparum survival during the intraerythrocytic developmental cycle (IDC), yet the transcriptional regulatory mechanisms that coordinate this process remain poorly understood. Here, we identify the ApiAP2 transcription factor PfAP2-host cell remodeling (HCR) as a key regulator of ring-stage development. Conditional truncation of pfap2-hcr that removes both the AP2 domain-encoding sequences halts parasite progression during ring-stage development, indicating an essential role during ring maturation. Loss of PfAP2-HCR led to disrupted expression of host cell remodeling genes, absence of Maurers clefts, and collapse of the export apparatus. Integrated RNA-seq and ChIP- seq analyses revealed that PfAP2-HCR directly or indirectly regulates 93 of 305 (30%) exported proteins, including 27 known essential factors and key parasitophorous vacuole membrane components such as Exp1 and the PTEX core protein Exp2. PfAP2-HCR is also associated with PfAP2-P, PfMORC, and PfISWI, placing it within a broader chromatin-linked regulatory network. Given its expression in multiple life-cycle stages, including gametocytes and sporozoites, PfAP2-HCR may coordinate the host cell remodeling processes beyond the blood stages. These findings position PfAP2-HCR as a central transcriptional hub that drives the expression of key pathogenic factors required to remodel a terminally differentiated host cell for parasite survival and growth.