The Plasmodium falciparum Raf Kinase Inhibitor Protein is Essential for Red Blood Cell Invasion and Can Be Functionally Substituted by Host RKIP

Raf kinase inhibitor protein (RKIP) plays a key role in regulating critical signaling pathways in higher eukaryotes. We previously demonstrated that Plasmodium falciparum RKIP (PfRKIP) modulates the activity of PfCDPK1, a key regulator of red blood cell invasion. Here, we have used a pharmacological approach to investigate the function of PfRKIP. Locostatin, a mammalian RKIP inhibitor, shows a dose-dependent decrease in RBC invasion. Mechanistically, locostatin increases the interaction between PfRKIP and PfCDPK1, thereby sequestering PfCDPK1 in a complex preventing substrate phosphorylation. Surprisingly, PfRKIP could be knocked out from the parasite without any perceptible growth defect. Interestingly, the PfRKIP-deficient parasites show an increase in the import of host RKIP. Like the parasite RKIP, the host RKIP interacts with PfCDPK1 and is associated with high-molecular-weight complexes comprising PfCDPK1 suggesting functional complementation by the host RKIP in the PfRKIP null parasites. As expected, locostatin shows similar inhibitory effect on the knock-out parasites as the WT. Our study reveals a novel host-parasite interaction wherein the parasite co-opts host proteins to maintain critical signaling pathways. Targeting the PfRKIP signaling axis, along with the host proteins, represents a potential strategy for anti-malarial drug development that is conceptually less prone to parasite-driven resistance development.