Deletion of pfap2-mrp before the first peak of expression at 16 h.p.i. affects parasite development beyond late trophozoite/early schizont stages. Deletion of pfap2-mrp well before 40 h.p.i. but after the first peak of expression at 16 h.p.i. affects merozoite development and blocks parasite egress from infected RBCs. At this late stage of intraerythrocytic development, the second peak of pfap2-mrp expression activates many genes associated with invasion, egress, antigenic variation, host cell remodeling and protein phosphorylation, either directly by binding to their promoter or indirectly through other downstream ApiAP2 transcription factors and regulators. PfAP2-MRP is a direct repressor of var genes and an indirect repressor of many gametocytogenesis-associated marker genes. Deletion of pfap2-mrp derepresses expression of most of var genes leading to the displayed of the corresponding PfEMP1 on the iRBC surface. PfAP2-MRP acts as a direct activator of many other genes such as rifins, stevors, and pfmc-2tms coding for antigenically variant proteins, and binds to the promoter of 14 other ApiAP2s (50% of all P. falciparum ApiAP2 genes), suggesting that it is an upstream regulator of gene expression cascades during the IDC. PfAP2-MRP associates with many known and putative histone modifiers and chromatin remodelers that probably participate in PfAP2-MRP associated gene regulation. Altogether, PfAP2-MRP regulates the expression of most known pathogenic factors (associated with antigenic variation and parasite growth) in P. falciparum suggesting it is a master regulator of malaria pathogenesis.

Subudhi AK, Green JL, Satyam R, Lenz T, Salunke RP, Shuaib M, Isaioglou I, Abel S, Gupta M, Esau L, Mourier T, Nugmanova R, Mfarrej S, Sivapurkar R, Stead Z, Rached FB, Otswal Y, Sougrat R, Dada A, Kadamany AF, Fischle W, Merzaban J, Knuepfer E, Ferguson DJP, Gupta I, Le Roch KG, Holder AA, Pain A. PfAP2-MRP DNA-binding protein is a master regulator of parasite pathogenesis during malaria parasite blood stages. bioRxiv [Preprint]. 2023 May. PMID: 37293082

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